Corneal UlcerPhase 3CLAIRNCT02570321
Cross-linking for Corneal Ulcers Treatment Trial
A Phase 3 study testing Corneal Cross-linking and Anti Fungal Drug in people with Corneal Ulcer and Infectious Keratitis, run by University of California, San Francisco at 2 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Corneal Ulcer, Infectious Keratitis, Bacterial Ulcer
- What is being tested?
- Corneal Cross-linking and Anti Fungal Drug
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 147 participants
- Where
- 2 sitesin 2 countries
- Study dates
- Nov 2015to 19 Mar 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United States1 site
Proctor Foundation, UCSF
San Francisco, California, 94143
About this study
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
- Corneal Ulcer, Infectious Keratitis, Bacterial Ulcer, Fungal Ulcer
- Being tested
- Corneal Cross-linking, Anti Fungal Drug
- Keywords
- Cornea, Ulcer, Infectious keratitis, Bacterial, Fungal
- Medical subject headings
- Corneal Ulcer, Corneal Diseases, Ulcer
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Corneal Cross-linkingProcedure or surgery
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.
Anti Fungal DrugDrug
Topical Amphotericin B vs Topical Natamycin
| Study group | Role | What they receive |
|---|---|---|
| Bacterial ulcer cross-linking | Experimental | Standard of care topical treatment for bacterial ulcer plus cross-linking Receives: Procedure: Corneal Cross-linking |
| Bacterial ulcer control | Active comparator | Standard of care topical treatment for bacterial ulcer Receives: Procedure: Corneal Cross-linking |
| Fungal ulcer cross-linking plus natamycin | Experimental | Standard of care topical treatment for fungal ulcer with natamycin plus cross-linking Receives: Procedure: Corneal Cross-linking; Drug: Anti Fungal Drug |
| Fungal ulcer control with natamycin | Active comparator | Standard of care topical treatment for fungal ulcer with natamycin Receives: Procedure: Corneal Cross-linking; Drug: Anti Fungal Drug |
| Fungal ulcer cross-linking plus amphotericin | Experimental | Standard of care topical treatment for fungal ulcer with amphotericin plus cross-linking Receives: Procedure: Corneal Cross-linking; Drug: Anti Fungal Drug |
| Fungal ulcer control with amphotericin | Active comparator | Standard of care topical treatment for fungal ulcer with amphotericin Receives: Procedure: Corneal Cross-linking; Drug: Anti Fungal Drug |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 4 to 24 hours after enrollment
Secondary outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2015 (estimated)
- Study startNov 2015
- Primary completion18 Jun 2018
- Study completion19 Mar 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Corneal UlcerStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients with corneal ulcers are randomized to topical antimicrobial plus corneal crosslinking versus topical antimicrobial alone
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 147 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Aravind Eye Hospitals, India
- Responsible party
- Sponsor
- Investigators
- Jennifer R Rose-Nussbaumer, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02570321
- Sponsor's protocol ID
- 14-14918
- Acronym
- CLAIR
- Status last verified
- Jun 2025
- First submitted
- 15 Sep 2015
- Last updated
- 18 Jun 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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 35044972Prajna 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 35024776Prajna 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 33079921Prajna 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 33031809Davis 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 32557558Prajna 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 at a glance
From the registry record, last updated by the sponsor on 18 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cross-linking for Corneal Ulcers Treatment Trial
- ClinicalTrials.gov ID
- NCT02570321
- Acronym / sponsor ID
- CLAIR / 14-14918
- Conditions
- Corneal Ulcer, Infectious Keratitis, Bacterial Ulcer, Fungal Ulcer
- Keywords
- Cornea, Ulcer, Infectious keratitis, Bacterial, Fungal
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 147 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- Aravind Eye Hospitals, India
- Study start
- Nov 2015 (actual)
- Primary completion
- 18 Jun 2018 (actual)
- Study completion
- 19 Mar 2019 (actual)
- First posted
- 7 Oct 2015 (estimated)
- Results
- Posted 27 Aug 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 6
- Model description
- Patients with corneal ulcers are randomized to topical antimicrobial plus corneal crosslinking versus topical antimicrobial alone
| Arm | Type | Receives |
|---|---|---|
| Bacterial ulcer cross-linking | Experimental | Procedure: Corneal Cross-linkingStandard of care topical treatment for bacterial ulcer plus cross-linking |
| Bacterial ulcer control | Active comparator | Procedure: Corneal Cross-linkingStandard of care topical treatment for bacterial ulcer |
| Fungal ulcer cross-linking plus natamycin | Experimental | Procedure: Corneal Cross-linking, Drug: Anti Fungal DrugStandard of care topical treatment for fungal ulcer with natamycin plus cross-linking |
| Fungal ulcer control with natamycin | Active comparator | Procedure: Corneal Cross-linking, Drug: Anti Fungal DrugStandard of care topical treatment for fungal ulcer with natamycin |
| Fungal ulcer cross-linking plus amphotericin | Experimental | Procedure: Corneal Cross-linking, Drug: Anti Fungal DrugStandard of care topical treatment for fungal ulcer with amphotericin plus cross-linking |
| Fungal ulcer control with amphotericin | Active comparator | Procedure: Corneal Cross-linking, Drug: Anti Fungal DrugStandard of care topical treatment for fungal ulcer with amphotericin |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Corneal Cross-linkingFor 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. | Procedure or surgery | Bacterial ulcer control, Bacterial ulcer cross-linking, Fungal ulcer control with amphotericin, Fungal ulcer control with natamycin, Fungal ulcer cross-linking plus amphotericin, Fungal ulcer cross-linking plus natamycin |
| Anti Fungal DrugTopical Amphotericin B vs Topical Natamycin | Drug | Fungal ulcer control with amphotericin, Fungal ulcer control with natamycin, Fungal ulcer cross-linking plus amphotericin, Fungal ulcer cross-linking plus natamycin |
Primary outcome
Microbiological Cure on Repeat Culture
Time frame: 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.
3 secondary outcomes
Best Spectacle-corrected Visual Acuity
Time frame: 3 months
Scar Size
Time frame: 3 months
Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty
Time frame: 3 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35044972Prajna 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.
- Derived from this study: PubMed 35024776Prajna 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.
- Derived from this study: PubMed 33079921Prajna 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.
- Derived from this study: PubMed 33031809Prajna 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.
- Derived from this study: PubMed 32557558Davis 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.
- Derived from this study: PubMed 31619359Prajna 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jennifer R Rose-Nussbaumer, MD principal investigator
University of California, San Francisco
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Corneal Cross-linking and Anti Fungal Drug in people with Corneal Ulcer and Infectious Keratitis, run by University of California, San Francisco at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States, India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Aug 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Microbiological Cure on Repeat Culture (time frame: 4 to 24 hours after enrollment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02570321, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2025.