Corneal Collagen Crosslinking for Keratoconus

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Cornea and Laser Eye Institute

Disqualifiers: Pregnancy, Nystagmus, Corneal scarring, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method of corneal collagen crosslinking (CXL) to treat keratoconus and corneal ectasia. These conditions cause the cornea, the clear front layer of the eye, to thin and change shape, affecting vision. The trial compares two methods of applying riboflavin (vitamin B2) drops during the procedure to determine which is more effective. It targets individuals diagnosed with keratoconus or corneal ectasia who struggle to see clearly even with glasses or contact lenses and have a certain corneal thickness. Participants should not have other eye conditions that could complicate healing. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinator or your doctor for guidance.

What prior data suggests that corneal collagen crosslinking is safe for treating keratoconus?

Research has shown that riboflavin, used in a procedure called corneal collagen crosslinking, is generally safe. In studies, patients with eye conditions like keratoconus who received riboflavin and UV light treatment did not experience serious side effects. Most side effects are mild, such as eye discomfort or sensitivity to light, and these usually resolve within a few days.

The procedure involves applying riboflavin drops to the eye and then shining UV light on it to strengthen the cornea. The FDA has approved this method for treating similar eye conditions, indicating its safety. Research also suggests that not removing the outer layer of the cornea (a method called transepithelial crosslinking) may reduce the risk of infection and aid faster recovery, making the process more comfortable.

Overall, current evidence supports the safety of using riboflavin in corneal treatments, with studies showing its use in hundreds of patients without major problems. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about corneal collagen crosslinking with riboflavin for keratoconus because it strengthens the cornea and can halt the progression of the disease. Unlike conventional treatments that primarily focus on vision correction, such as glasses or contact lenses, this procedure actually reinforces the corneal structure itself. The unique aspect of this treatment involves the use of riboflavin drops combined with UV light to create new collagen bonds, improving the cornea's rigidity. This innovative approach targets the root cause of keratoconus, offering a more sustainable long-term solution and potentially reducing the need for corneal transplants in advanced cases.

What evidence suggests that corneal collagen crosslinking is effective for keratoconus?

Research has shown that corneal collagen crosslinking (CXL) with riboflavin can effectively slow or stop the progression of keratoconus and corneal ectasia. Studies have found that this treatment can reduce corneal curvature and astigmatism, often improving vision. Riboflavin strengthens the cornea, enhancing its stability. In this trial, participants will receive riboflavin drops either every minute or every two minutes during UV exposure. Past patients have experienced corneal stabilization and flattening with this treatment. Overall, CXL with riboflavin is considered a promising approach to managing these eye conditions. ^{2 6 7 8 9}

Who Is on the Research Team?

Peter Hersh, MD

Principal Investigator

Cornea and Laser Eye Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with keratoconus or corneal ectasia, where the thinnest part of their cornea is more than 375 microns thick. They should have vision worse than 20/20 even with glasses or contacts. People can't join if they're allergic to study drugs, pregnant, nursing, have certain eye conditions that affect healing or gaze stability, very thin corneas (≤350 microns), or significant scarring in the treatment area.

Inclusion Criteria

Corneal thickness greater than 375 microns at the thinnest point

I have been diagnosed with keratoconus or corneal ectasia after surgery.

Vision with contact lenses or glasses is worse than 20/20

Exclusion Criteria

I don't have any health issues that would slow down my skin healing.

Corneal pachymetry ≤ 350 microns at the thinnest point measured by Pentacam in the eye(s) to be treated

I have had an eye condition that could cause future problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo transepithelial corneal collagen crosslinking with riboflavin administration every 1 or 2 minutes during UV exposure

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness, including assessments of visual acuity, endothelial cell density, and keratometry

12 months

Multiple visits at 1, 3, 6, and 12 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Riboflavin

Trial Overview The trial tests a safer version of corneal collagen crosslinking called Transepithelial CXL using Riboflavin. Unlike traditional methods which remove surface cells and increase infection risk, this method keeps them intact for better safety and quicker recovery.

How Is the Trial Designed?

Group I: Riboflavin drops every minute Active Control 1 Intervention

Administration of riboflavin every 2 minutes for the duration of UV exposure.

Group II: Riboflavin drops every 2 minutes Active Control 1 Intervention

Administration of riboflavin every 1 minute for the duration of UV exposure.

Riboflavin is already approved in United States, European Union for the following indications:

Approved in United States as Riboflavin ophthalmic solution for:

• Progressive keratoconus
• Corneal ectasia following refractive surgery

Approved in European Union as Riboflavin ophthalmic solution for:

• Progressive keratoconus
• Corneal ectasia following refractive surgery

Who Is Running the Clinical Trial?

Cornea and Laser Eye Institute

Lead Sponsor

Trials

10

Recruited

1,100+

Published Research Related to This Trial

In a study involving 7 patients with progressive keratoconus, high-fluence corneal collagen cross-linking (CXL) at 18 mW/cm² for 5 minutes did not significantly affect endothelial cell density or the speed of epithelial healing, indicating a favorable safety profile.

No significant changes were observed in keratometric readings or corrected distance visual acuity at 1 and 6 months postoperatively, suggesting that while the preliminary results are promising, further research is needed to fully evaluate the efficacy of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. Gatzioufas, Z., Richoz, O., Brugnoli, E., et al.[2022]

A study involving 100 eyes from 61 patients with progressive keratoconus found that both 0.1% riboflavin solutions used in corneal collagen crosslinking (CXL) were equally safe and effective, with no significant differences in visual and corneal measurements after 12 months.

No serious complications occurred in either group during or after the procedure, indicating that both riboflavin solutions can be safely used for treating keratoconus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective, Comparative, Clinical Study to Evaluate the Safety and Efficacy of Two Different 0.1% Riboflavin Solutions Used in Collagen Crosslinking Treatment for Patients with Keratoconus. Brar, S., Ganesh, S., Reddy, SS., et al.[2022]

Corneal collagen cross-linking (CXL) using dextran-free isotonic riboflavin solution is a safe treatment for keratoconus, with no reported intraoperative or postoperative complications in a study of 26 patients.

At a 6-month follow-up, patients showed significant improvements in best corrected visual acuity and reductions in maximum keratometry and corneal thickness, indicating effective short-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Six-month outcomes of corneal crosslinking with dextran-free isotonic riboflavin solution. Oltulu, R., Satirtav, G., Donbaloglu, M., et al.[2017]

Both the Sina Darou and Uznach formulations of Riboflavin were found to be equally effective in improving visual acuity and corneal topography in 60 keratoconus patients after 6 months of corneal collagen cross-linking (CXL).

The Sina Darou formulation resulted in a greater decrease in corneal hysteresis compared to the Uznach formulation, suggesting potential differences in their effects on corneal biomechanical properties, which will be further evaluated in long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of clinical results of two pharmaceutical products of riboflavin in corneal collagen cross-linking for keratoconus. Hashemi, H., Seyedian, MA., Miraftab, M., et al.[2021]

In a study involving 25 eyes from 21 patients, combining corneal collagen cross-linking with riboflavin (C3-R) with inferior-segment Intacs significantly improved keratoconus outcomes compared to Intacs alone, showing greater reductions in cylinder measurements and keratometry values.

The results indicate that the addition of C3-R enhances the effectiveness of Intacs in treating keratoconus, leading to better overall corneal shape and stability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of inferior-segment Intacs with and without C3-R on keratoconus. Chan, CC., Sharma, M., Wachler, BS.[2022]

In a study of 49 eyes from 47 patients with progressive keratoconus and thin corneas, both corneal collagen crosslinking (CXL) with hypoosmolar riboflavin and standard CXL showed significant improvements in uncorrected and best-corrected visual acuity after 3 years, with no significant differences between the two methods.

Both treatment groups demonstrated safety, as there was no significant endothelial cell loss or sight-threatening complications, and no progression of keratoconus was observed in any patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term visual, refractive, tomographic and aberrometric outcomes of corneal collagen crosslinking (CXL) with or without hypoosmolar riboflavin solution in the treatment of progressive keratoconus patients with thin corneas. Celik Buyuktepe, T., Ucakhan, OO.[2022]

Accelerated corneal collagen crosslinking (CXL) with riboflavin showed significant improvement in uncorrected distance visual acuity and reduced maximum keratometry readings in 39 eyes of 22 patients over a 6-month period, indicating its effectiveness in treating keratoconus.

The study found no significant changes in endothelial cell density post-treatment, suggesting that accelerated CXL is a safe option that does not adversely affect corneal health while effectively halting the progression of keratoconus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-irradiance accelerated collagen crosslinking for the treatment of keratoconus: six-month results. Mita, M., Waring, GO., Tomita, M.[2022]

In a study of 57 eyes from 55 patients with progressive keratoconus, corneal crosslinking (CXL) with riboflavin led to significant improvements in best corrected visual acuity and reductions in key corneal measurements over a 24-month follow-up period.

CXL was effective in stabilizing keratoconus, as evidenced by a decrease in keratometry readings and corneal volume, while maintaining its efficacy even as the cornea began to recover its original volume after the initial treatment phase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term results of corneal collagen crosslinking for progressive keratoconus. De Bernardo, M., Capasso, L., Lanza, M., et al.[2022]

Corneal collagen cross-linking (CXL) using riboflavin and UV light is a safe and effective treatment for keratoconus, showing significant improvements in uncorrected visual acuity from a mean of 1.18 to 0.46 logarithm of the minimum angle of resolution over 12 months in a study of 10 eyes.

The procedure also resulted in significant reductions in keratometry values and spherical equivalent, indicating a decrease in corneal steepness and improved corneal shape, with 80% of eyes showing decreased elevation values, although long-term follow-up is necessary to fully assess its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riboflavin/Ultraviolet A corneal collagen cross-linking for the treatment of keratoconus: visual outcomes and Scheimpflug analysis. Henriquez, MA., Izquierdo, L., Bernilla, C., et al.[2022]

In a study of 23 eyes from 13 patients with progressive keratoconus, riboflavin-UV-A corneal collagen cross-linking (CXL) significantly improved uncorrected and best spectacle-corrected visual acuity after 12 months, indicating its efficacy in managing this condition.

The procedure also stabilized corneal shape by flattening the steepest keratometry readings, while showing no significant adverse effects on intraocular pressure or endothelial cell count, suggesting it is a safe treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Corneal collagen cross-linking in the treatment of progressive keratoconus-preliminary results]. Li, G., Fan, ZJ., Peng, XJ.[2014]

In a study involving 20 eyes of 19 patients, riboflavin-UV-A cross-linking significantly improved uncorrected visual acuity by an average of 4.15 lines and best corrected visual acuity by 1.65 lines after one year, indicating its effectiveness in treating keratoconus.

The treatment also stabilized corneal shape, with a reduction in keratometry readings and improvements in corneal symmetry, demonstrating that this method not only enhances vision but also addresses the underlying issues of keratoconus safely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: One-year results. Arbelaez, MC., Sekito, MB., Vidal, C., et al.[2022]

Corneal cross-linking using riboflavin and UV light is a safe procedure, as none of the patients experienced a loss in best spectacle corrected visual acuity (BSCVA) after treatment.

The treatment effectively halted the progression of keratoconus in all patients, with a notable reduction in corneal curvature and improvements in unaided visual acuity over six months, although some changes were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Corneal Cross-linking for the treatment of keratoconus: preliminary results]. Jankov, MR., Hafezi, F., Beko, M., et al.[2019]

In a long-term study of 44 keratoconic eyes treated with riboflavin ultraviolet A collagen cross-linking, the procedure demonstrated significant stability of keratoconus over an average follow-up of 52.4 months, with no major side effects reported.

Patients experienced notable improvements in visual acuity, with an average increase of 1.9 Snellen lines for best spectacle-corrected vision and 2.7 lines for uncorrected vision, alongside reductions in corneal irregularities and aberrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Caporossi, A., Mazzotta, C., Baiocchi, S., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6644189/

Safety and efficacy of riboflavin-assisted collagen cross ... First, riboflavin increases cross-linking and second, it serves as a protective shield to other deep ocular structures.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6436846/

An Investigation of the Effects of Riboflavin Concentration on ... Our results demonstrate a dose-response curve with increasing riboflavin solution concentrations up to 0.3% achieving greater CXL efficacy.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03095235?term=AREA%5BBasicSearch%5D(RIBOFLAVIN)&rank=4

Dietary Riboflavin (Vitamin B-2) and Cornea Cross-Linking These patients reported no adverse effects and preliminary results showed corneal stabilization and/or corneal flattening in all 7 patients It is hypothesized ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1350946224000417

Crosslinking with UV-A and riboflavin in progressive ... Corneal collagen cross-linking (CXL) represents a technique to slow or even halt the progression of ectatic pathologies.

5. medrxiv.org medrxiv.org/content/10.1101/2022.02.05.22270507.full

Long-term outcome of corneal collagen crosslinking with ... All of these studies showed a decrease in corneal curvature and astigmatism and an improvement in visual acuity. Aim of this study was to assess ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2016/203324Orig1s000Lbl.pdf

203324Orig1s000 - accessdata.fda.gov conducted to evaluate the safety and effectiveness of riboflavin ophthalmic solution/UVA irradiation for performing corneal collagen cross-linking. These ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01459679

Safety & Efficacy of Corneal Collagen Cross-Linking in ... The objectives of this study are to evaluate and compare the safety and efficacy of three treatment regimens for corneal collagen cross-linking performed ...

8. glaukos.com glaukos.com/prescribing-information/photrexa-viscous-and-photrexa/

Photrexa® Viscous & Photrexa® | Prescribing Information Safety data were obtained from: 193 randomized CXL study eyes (102 keratoconus ... riboflavin ophthalmic solution/UVA irradiation for performing corneal collagen ...

9. aoa.org aoa.org/AOA/Documents/Approved_PI.pdf

FULL PRESCRIBING INFORMATION Safety data were obtained from 193 randomized CXL study eyes, 191 control eyes, and 319 nonrandomized. CXL non-study eyes. Overall, 512 eyes in 364 patients ...