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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called corneal collagen crosslinking (CXL) for individuals with keratoconus or corneal ectasia. These conditions cause the cornea, the clear front part of the eye, to thin and take on a cone shape, affecting vision. The trial compares two methods of applying riboflavin (vitamin B2) drops during UV light exposure to determine which is more effective and comfortable. Individuals experiencing worsening vision due to these conditions might be suitable for the trial. Contact lens wearers must stop using them for a week before joining. As a Phase 3 trial, this treatment is in the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that riboflavin, used in corneal collagen crosslinking (CXL), is generally safe for treating eye conditions like keratoconus and corneal ectasia. In studies involving over 500 eyes, riboflavin was well-tolerated. It strengthens the cornea and protects the inner parts of the eye. Most participants did not experience serious side effects. Some reported mild discomfort or irritation, which is common with eye treatments. Overall, riboflavin eye drops in CXL have a strong safety record, making them a reliable choice for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about corneal collagen crosslinking with riboflavin for keratoconus because it promises a more efficient and potentially more effective treatment approach. Unlike traditional methods that often involve rigid contact lenses or corneal transplants, this treatment uses riboflavin drops combined with UV light to strengthen corneal tissue. The trial explores different dosing intervals of riboflavin drops, every 2 minutes versus every 10 minutes, to potentially enhance the procedure's effectiveness and patient comfort. This technique not only targets the root cause by stabilizing the cornea but also might offer quicker recovery and better long-term outcomes.

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

Research has shown that riboflavin-assisted corneal collagen crosslinking (CXL) effectively treats keratoconus. Studies have found it can slow or even halt the progression of the condition, particularly in younger individuals, helping to prevent vision loss. Additionally, results indicate a reduction in corneal curvature and improved eyesight. In this trial, participants will receive riboflavin drops at intervals of either every 2 minutes or every 10 minutes during UV exposure to assess the effectiveness of these dosing schedules. Riboflavin strengthens the cornea and protects deeper parts of the eye. Patients have reported more stable and flatter corneas, with no major side effects. Overall, riboflavin CXL is considered a safe and promising treatment for keratoconus. ^{3 6 7 8 9}

Who Is on the 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

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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 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]

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]

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 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]

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]

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]

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.

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 ...

3.

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 ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S1350946224000417

Crosslinking with UV-A and riboflavin in progressive ...

Cross-linking is safe; slows or even halts the progression of ectasia, which is most important in younger keratoconus patients to prevent vision loss.

5.

onlinelibrary.wiley.com

onlinelibrary.wiley.com/doi/10.1002/jbio.202500432

Assessing Effects of Riboflavin/UV‐A Cross‐Linking on ...

After CXL, the relative increase in corneal stiffness compared to untreated eyes was reported as 86% and 79% at 20 and 30 mmHg, respectively [57] ...

6.

glaukos.com

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

Photrexa® Viscous & Photrexa® | Prescribing Information

Three prospective, randomized, parallel-group, open-label, sham-controlled trials were conducted to evaluate the safety and effectiveness of riboflavin ...

7.

mayoclinic.org

mayoclinic.org/drugs-supplements/riboflavin-5-phosphate-ophthalmic-route/description/drg-20235484

Riboflavin 5-phosphate (ophthalmic route) - Side effects & ...

Riboflavin 5-Phosphate eye drops is a photoenhancer used in ... keratoconus and corneal ectasia following refractive surgery.

8.

accessdata.fda.gov

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

203324Orig1s000 - accessdata.fda.gov

Safety data were obtained from 193 randomized CXL study eyes ... conducted to evaluate the safety and effectiveness of riboflavin ophthalmic solution/UVA.

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 ...