Corneal Collagen Crosslinking for Keratoconus

Overseen By Peter Hersh, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Cornea and Laser Eye Institute

Disqualifiers: Corneal disease, Pregnancy, Nystagmus, 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: 1

Duration: 1 day

160 Participants Needed

Trial Summary

What is the purpose of this trial?

Corneal collagen crosslinking (CXL) has been demonstrated 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. 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 and scarring, faster visual recovery and improved patient comfort in the early postoperative healing period.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. However, contact lens wearers must stop wearing them for 1 week before the screening.

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

Research shows that corneal collagen cross-linking with riboflavin and UV-A light is effective in improving vision and stabilizing keratoconus, a condition where the cornea (the clear front part of the eye) becomes thin and cone-shaped. Studies have reported both short-term and long-term benefits, indicating that this treatment can help manage the progression of keratoconus. ^{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. ^{1 6 7 8 9}

How is the treatment for keratoconus using riboflavin unique?

Corneal collagen crosslinking with riboflavin is unique because it strengthens the cornea by using a combination of riboflavin (Vitamin B2) and ultraviolet-A light, which helps to halt the progression of keratoconus, a condition where the cornea becomes thin and cone-shaped. This treatment is different from other options as it directly targets the structural integrity of the cornea rather than just correcting vision. ^{8 10 11 12 13}

Research Team

Peter S Hersh, MD

Principal Investigator

Cornea and Laser Eye Institute - Hersh Vision Group

Steven A Greenstein, MD

Principal Investigator

Cornea and Laser Eye Institute - Hersh Vision Group

Eligibility Criteria

This trial is for people aged 12 or older with keratoconus or corneal ectasia, evidenced by specific patterns on a corneal map. Participants must not wear contact lenses for a week before the study and be willing to follow up. It's not for those with significant scarring in the treatment area, very thin corneas, pregnant or nursing women, certain histories of eye disease, conditions affecting epithelial healing, unstable gaze during treatment, or known drug sensitivities.

Inclusion Criteria

I am 12 years old or older.

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

My eye condition is related to keratoconus or corneal ectasia after surgery.

Exclusion Criteria

I have a history of corneal disease.

A known sensitivity to study medications

Corneal pachymetry measuring 300 microns or less at the thinnest point measured by Pentacam in the eye(s) to be treated

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 2 or 10 minutes during UV exposure

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of keratometry and visual acuity

12 months

Regular visits as per study protocol

Treatment Details

Interventions

• Riboflavin

Trial Overview The trial tests an 'Epi-on' version of Corneal Collagen Crosslinking (CXL) using Riboflavin (Vitamin B2). Unlike traditional CXL where the top layer of the cornea is removed, this method keeps it intact which may reduce infection risk and improve recovery time while treating keratoconus and post-surgery ectasia.

Participant Groups

Group I: Riboflavin drop every 2 minutes Active Control 1 Intervention

Administration of one drop of Riboflavin every 2 minutes during UV exposure

Group II: Riboflavin drop every 10 minutes Active Control 1 Intervention

Administration of one drop of Riboflavin every 10 minutes during 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

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]

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]

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 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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. Brazil pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. Spain pubmed.ncbi.nlm.nih.gov

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

5. India pubmed.ncbi.nlm.nih.gov

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

11. Brazil pubmed.ncbi.nlm.nih.gov

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

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

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

13. 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]