CompletedNCT02570321CLAIRUpdated Jun 18, 2025Results posted

Cross-linking for Corneal Ulcers Treatment Trial

A Phase 3 interventional study of Corneal Cross-linking and Anti Fungal Drug in Corneal Ulcer, Infectious Keratitis and Bacterial Ulcer, sponsored by University of California, San Francisco. Completed at 2 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-06-18.

Sponsored by University of California, San Francisco · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 147
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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:

collagen cross-linking + amphotericin;
collagen cross-linking + natamycin;
amphotericin alone;
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.

Conditions studied

Corneal Ulcer
Infectious Keratitis
Bacterial Ulcer
Fungal Ulcer

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Keywords

Cornea
Ulcer
Infectious keratitis
Bacterial
Fungal

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts 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

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

Study design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Outcomes assessor)
Enrollment: 147 participants (actual)

Study arms

Experimental
Bacterial ulcer cross-linking
Standard of care topical treatment for bacterial ulcer plus cross-linking
Procedure: Corneal Cross-linking
Active comparator
Bacterial ulcer control
Standard of care topical treatment for bacterial ulcer
Procedure: Corneal Cross-linking
Experimental
Fungal ulcer cross-linking plus natamycin
Standard of care topical treatment for fungal ulcer with natamycin plus cross-linking
Procedure: Corneal Cross-linking · Drug: Anti Fungal Drug
Active comparator
Fungal ulcer control with natamycin
Standard of care topical treatment for fungal ulcer with natamycin
Procedure: Corneal Cross-linking · Drug: Anti Fungal Drug
Experimental
Fungal ulcer cross-linking plus amphotericin
Standard of care topical treatment for fungal ulcer with amphotericin plus cross-linking
Procedure: Corneal Cross-linking · Drug: Anti Fungal Drug
Active comparator
Fungal ulcer control with amphotericin
Standard of care topical treatment for fungal ulcer with amphotericin
Procedure: Corneal Cross-linking · Drug: Anti Fungal Drug

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

What researchers measure

Primary outcomes

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

Secondary outcomes

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
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
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

Other outcomes

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

Results

Posted Aug 27, 2024

Participant flow

Participant flow — Overall Study
Milestone	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Started	19	17	26	27	30	28
Completed	17	16	21	27	27	25
Not completed	2	1	5	0	3	3

Outcome measures

PrimaryMicrobiological 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
Reported as:: Count of participants · Participants

Microbiological Cure on Repeat Culture
Participants	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Culture negative	5	5	17	14	15	13
Culture positive	14	11	9	12	12	13

SecondaryBest 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
Reported as:: Median · logMar

Best Spectacle-corrected Visual Acuity
logMar	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Best Spectacle-corrected Visual Acuity	0.82 (0.62 to 1.4)	1.32 (0.43 to 1.75)	0.43 (0.1 to 0.72)	1 (0.3 to 1.8)	0.48 (0.2 to 1.7)	0.8 (0.5 to 1.24)

SecondaryScar 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
Reported as:: Mean · mm

Scar Size
mm	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Scar Size	3.5 (2.7 to 4.0)	3.0 (2.24 to 4.0)	3.0 (2.5 to 3.5)	3.9 (2.6 to 4.5)	3.5 (2.7 to 4.5)	3.1 (2.8 to 5.0)

SecondaryAdverse 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
Reported as:: Number · participants

Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty
participants	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Perforation	1	0	2	1	4	3
Therapeutic penetrating keratoplasty	3	1	5	5	5	3
Endophthalmitis	0	0	0	0	1	0
Median tarsorrhaphy	0	0	0	0	0	1

Other pre-specifiedVision 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
Reported as:: Median · score on a scale

Vision Related Quality of Life
score on a scale	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Vision Related Quality of Life	—	—	89.6 (71.9 to 100)	91.7 (75 to 100)	95.8 (72.9 to 100)	89.6 (71.9 to 100)

Adverse events

Collected over 3 months. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Bacterial Ulcer Control	0/19 (0%)	4/19 (21.1%)	0/19 (0%)
Bacterial Ulcer Cross-linking	0/17 (0%)	1/17 (5.9%)	0/17 (0%)
Fungal Ulcer Control With Natamycin	0/26 (0%)	7/26 (26.9%)	0/26 (0%)
Fungal Ulcer Cross-linking Plus Natamycin	0/27 (0%)	6/27 (22.2%)	0/27 (0%)
Fungal Ulcer Control With Amphotericin	0/30 (0%)	10/30 (33.3%)	0/30 (0%)
Fungal Ulcer Cross-linking Plus Amphotericin	0/28 (0%)	6/28 (21.4%)	1/28 (3.6%)

Most frequent serious events

Most frequent serious events
Event	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Therapeutic penetrating keratoplastyEye disorders	3/19	1/17	5/26	5/27	5/30	3/28
PerforationEye disorders	1/19	0/17	2/26	1/27	4/30	3/28
EndophthalmitisEye disorders	0/19	0/17	0/26	0/27	1/30	0/28

Most frequent other events

Most frequent other events
Event	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin
Median tarsorrhaphyEye disorders	0/19	0/17	0/26	0/27	0/30	1/28

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
Median	60 (54.5 to 65)	59 (48 to 66)	50 (36 to 55)	55 (47 to 65)	45 (40 to 58)	56 (45 to 65)	54.5 (45 to 64)

Sex: Female, Male
Sex: Female, Male(Participants)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
Female	6	9	9	12	16	11	63
Male	13	8	17	15	14	17	84

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	19	17	26	27	30	28	147
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0
White	0	0	0	0	0	0	0
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0

Region of Enrollment
Region of Enrollment(Participants)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
India	19	17	26	27	30	28	147

Occupation
Occupation(Participants)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
Agriculture	12	8	16	13	18	13	80
Nonagriculture	6	9	10	14	12	15	66
NA	1	0	0	0	0	0	1

Medication use at enrollment
Medication use at enrollment(Participants)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
Count of participants	8	10	18	21	19	24	100

Affected Eye
Affected Eye(Participants)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
Left	8	8	11	12	18	13	70
Right	11	9	15	15	12	15	77

Visual acuity
Visual acuity(LogMar)	Bacterial Ulcer Control	Bacterial Ulcer Cross-linking	Fungal Ulcer Control With Natamycin	Fungal Ulcer Cross-linking Plus Natamycin	Fungal Ulcer Control With Amphotericin	Fungal Ulcer Cross-linking Plus Amphotericin	Total
Mean	1.7 (0.7 to 1.7)	1.7 (0.9 to 1.8)	1.05 (0.62 to 1.12)	1.1 (0.6 to 1.7)	1.05 (0.62 to 1.7)	1.22 (0.91 to 1.7)	1.1 (0.63 to 1.7)

6 further baseline measures are reported on the registry.

Study locations

2 sites

Proctor Foundation, UCSF
San Francisco, California 94143, United States
Aravind Eye Hospitals
Madurai, Tamil Nadu, India

References and documents

Publications

Prajna NV, Radhakrishnan N, Lalitha P, Liu Z, Keenan JD, Arnold BF, Rose-Nussbaumer J. Mediators of the Effect of Corneal Cross-Linking on Visual Acuity for Fungal Ulcers: A Prespecified Secondary Analysis From the Cross-Linking-Assisted Infection Reduction Trial. Cornea. 2022 Oct 1;41(10):1217-1221. doi: 10.1097/ICO.0000000000002965. Epub 2022 Jan 17. PubMed 35044972 ↗
Prajna NV, Lalitha P, Krishnan T, Rajaraman R, Radnakrishnan N, Srinivasan M, Devi L, Das M, Liu Z, Zegans ME, Acharya NR, Porco TC, Lietman TM, Rose-Nussbaumer J. Patterns of Antifungal Resistance in Adult Patients With Fungal Keratitis in South India: A Post Hoc Analysis of 3 Randomized Clinical Trials. JAMA Ophthalmol. 2022 Feb 1;140(2):179-184. doi: 10.1001/jamaophthalmol.2021.5765. PubMed 35024776 ↗
Prajna NV, Radhakrishnan N, Lalitha P, Rajaraman R, Narayana S, Austin AF, Liu Z, Keenan JD, Porco TC, Lietman TM, Rose-Nussbaumer J. Cross-Linking Assisted Infection Reduction (CLAIR): A Randomized Clinical Trial Evaluating the Effect of Adjuvant Cross-Linking on Bacterial Keratitis. Cornea. 2021 Jul 1;40(7):837-841. doi: 10.1097/ICO.0000000000002510. PubMed 33079921 ↗
Prajna NV, Radhakrishnan N, Lalitha P, Austin A, Liu Z, Keenan JD, Porco TC, Lietman TM, Rose-Nussbaumer J. Cross-Linking Assisted Infection Reduction: One-year Follow-up of a Randomized Clinical Trial Evaluating Cross-Linking for Fungal Keratitis. Ophthalmology. 2021 Jun;128(6):950-952. doi: 10.1016/j.ophtha.2020.09.042. Epub 2020 Oct 5. No abstract available. PubMed 33031809 ↗
Davis SA, Bovelle R, Han G, Kwagyan J. Corneal collagen cross-linking for bacterial infectious keratitis. Cochrane Database Syst Rev. 2020 Jun 17;6(6):CD013001. doi: 10.1002/14651858.CD013001.pub2. PubMed 32557558 ↗
Prajna NV, Radhakrishnan N, Lalitha P, Austin A, Ray KJ, Keenan JD, Porco TC, Lietman TM, Rose-Nussbaumer J. Cross-Linking-Assisted Infection Reduction: A Randomized Clinical Trial Evaluating the Effect of Adjuvant Cross-Linking on Outcomes in Fungal Keratitis. Ophthalmology. 2020 Feb;127(2):159-166. doi: 10.1016/j.ophtha.2019.08.029. Epub 2019 Sep 4. PubMed 31619359 ↗

Study documents

Study protocol · Oct 4, 2016
Statistical analysis plan · May 28, 2019
Informed consent form · May 12, 2016

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT02570321
Lead sponsor: University of California, San Francisco
Collaborators: Aravind Eye Hospitals, India
Responsible party: Sponsor
First posted: Oct 7, 2015
Start date: Nov 2015
Primary completion: Jun 18, 2018
Completion: Mar 19, 2019
Results posted: Aug 27, 2024
Last update: Jun 18, 2025

Study contacts

Jennifer R Rose-Nussbaumer, MD

principal investigator · University of California, San Francisco

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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