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

160 Participants Needed

Trial Summary

What is the purpose of this trial?

Corneal collagen crosslinking (CXL) has been proposed as an effective method of reducing progression of both keratoconus and corneal ectasia after surgery, as well as possibly decreasing the steepness of the cornea in these pathologies. During previous studies of the CXL procedure, the surface epithelial cells have been removed. Transepithelial crosslinking in which the epithelium is not removed has been proposed to offer a number of advantages over traditional crosslinking including an increased safety profile by reducing the risk for infection as no epithelial barrier will be broken, faster visual recovery and improved patient comfort in the early postoperative healing period.

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 data supports the effectiveness of the treatment Riboflavin, Vitamin B2, Riboflavin ophthalmic solution for keratoconus?

Research shows that using riboflavin with UV-A light in corneal collagen cross-linking helps improve vision and stabilize keratoconus, a condition where the cornea becomes thin and cone-shaped. Studies have reported both short-term and long-term benefits, making it a promising treatment option. ^{1 2 3 4 5}

Is corneal collagen crosslinking with riboflavin safe for humans?

Research shows that corneal collagen crosslinking with riboflavin is generally safe for treating keratoconus, with studies evaluating its safety and effectiveness in humans. ^{3 6 7 8 9}

How is corneal collagen crosslinking with riboflavin unique for treating keratoconus?

Corneal collagen crosslinking with riboflavin is unique because it strengthens the cornea by using a combination of riboflavin (a type of vitamin B2) and ultraviolet light, which helps to stop the progression of keratoconus, a condition where the cornea becomes thin and cone-shaped. This treatment is different from others as it directly targets the corneal structure to improve its stability, rather than just correcting vision. ^{8 10 11 12 13}

Research Team

Peter Hersh, MD

Principal Investigator

Cornea and Laser Eye Institute

Eligibility Criteria

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 am 18 years old or older.

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

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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]

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 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]

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]

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]

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]

References

1. Spain pubmed.ncbi.nlm.nih.gov

Long-term results of corneal collagen crosslinking for progressive keratoconus. [2022]

2. India pubmed.ncbi.nlm.nih.gov

Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: One-year results. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Comparison of clinical results of two pharmaceutical products of riboflavin in corneal collagen cross-linking for keratoconus. [2021]

4. Brazil pubmed.ncbi.nlm.nih.gov

[Corneal Cross-linking for the treatment of keratoconus: preliminary results]. [2019]

5. United States 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. [2022]

6. New Zealand 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. [2022]

7. China pubmed.ncbi.nlm.nih.gov

[Corneal collagen cross-linking in the treatment of progressive keratoconus-preliminary results]. [2014]

8. United States pubmed.ncbi.nlm.nih.gov

Effect of inferior-segment Intacs with and without C3-R on keratoconus. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Riboflavin/Ultraviolet A corneal collagen cross-linking for the treatment of keratoconus: visual outcomes and Scheimpflug analysis. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. [2022]

11. Germany 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. [2022]

12. Brazil pubmed.ncbi.nlm.nih.gov

Six-month outcomes of corneal crosslinking with dextran-free isotonic riboflavin solution. [2017]

13. United States pubmed.ncbi.nlm.nih.gov

High-irradiance accelerated collagen crosslinking for the treatment of keratoconus: six-month results. [2022]