Cross-linking for Corneal Ulcers Treatment Trial (CLAIR)

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.

Study Overview

• Status: Completed
• Conditions: Corneal Ulcer; Infectious Keratitis; Bacterial Ulcer; Fungal Ulcer
• Intervention / Treatment: Procedure: Corneal Cross-linking; Drug: Anti Fungal Drug

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.

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bacterial ulcer cross-linking; Standard of care topical treatment for bacterial ulcer plus cross-linking	Procedure: Corneal 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.
Active Comparator: Bacterial ulcer control; Standard of care topical treatment for bacterial ulcer	Procedure: Corneal 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.
Experimental: Fungal ulcer cross-linking plus natamycin; Standard of care topical treatment for fungal ulcer with natamycin plus cross-linking	Procedure: Corneal 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.; Drug: Anti Fungal Drug; Topical Amphotericin B vs Topical Natamycin
Active Comparator: Fungal ulcer control with natamycin; Standard of care topical treatment for fungal ulcer with natamycin	Procedure: Corneal 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.; Drug: Anti Fungal Drug; Topical Amphotericin B vs Topical Natamycin
Experimental: Fungal ulcer cross-linking plus amphotericin; Standard of care topical treatment for fungal ulcer with amphotericin plus cross-linking	Procedure: Corneal 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.; Drug: Anti Fungal Drug; Topical Amphotericin B vs Topical Natamycin
Active Comparator: Fungal ulcer control with amphotericin; Standard of care topical treatment for fungal ulcer with amphotericin	Procedure: Corneal 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.; Drug: Anti Fungal Drug; Topical Amphotericin B vs Topical Natamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	4 to 24 hours after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Aravind Eye Hospitals, India
• Investigators: Principal Investigator: Jennifer R Rose-Nussbaumer, MD, University of California, San Francisco

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): June 18, 2018
• Study Completion (Actual): March 19, 2019

Study Registration Dates

• First Submitted: September 15, 2015
• First Submitted That Met QC Criteria: October 6, 2015
• First Posted (Estimated): October 7, 2015

Study Record Updates

• Last Update Posted (Actual): June 18, 2025
• Last Update Submitted That Met QC Criteria: June 16, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Cornea; Ulcer; Bacterial; Fungal; Infectious keratitis
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Eye Diseases; Corneal Diseases; Eye Infections; Ulcer; Infections; Communicable Diseases; Corneal Ulcer; Keratitis; Anti-Infective Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Anti-Infective Agents, Local; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; 14-alpha Demethylase Inhibitors; Antifungal Agents; Clotrimazole; Miconazole
• Other Study ID Numbers: 14-14918

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No