Corneal Collagen Crosslinking for Keratoconus

Overseen By Stacey Lazar

Age: 18+

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 new method for treating keratoconus and corneal ectasia, conditions that cause the cornea to bulge and curve out of shape. The goal is to determine if pulsed UVA light during corneal collagen crosslinking can enhance treatment effectiveness by increasing oxygen in the eye. Participants receive a special eye drop, riboflavin (Vitamin B2 Ophthalmic Solution), combined with either continuous or pulsed UVA light. Suitable candidates are adults diagnosed with keratoconus or corneal ectasia, with significant corneal steepness or bulging. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

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. It's best to discuss this with the trial team or your doctor.

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

Research has shown that corneal collagen crosslinking, which uses riboflavin (a type of vitamin B2) and UVA light, is generally safe for treating conditions like keratoconus. One study found that both continuous and pulsed UVA light methods are well-tolerated by patients. Most side effects, such as eye redness and discomfort, are mild and temporary, while serious side effects are rare. The FDA has also approved this treatment for other eye conditions, indicating a strong safety record. This approval suggests it is safe for similar treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about corneal collagen crosslinking for keratoconus because it offers a unique approach compared to standard treatments like glasses, contact lenses, or corneal transplants. The treatment uses riboflavin (vitamin B2) combined with UVA light to strengthen the cornea by creating new crosslinks between collagen fibers, which can halt or slow the progression of keratoconus. The trial is examining two methods: continuous UVA light for a shorter duration and pulsed UVA light for a longer time. Both methods aim to enhance corneal stability more effectively and with potentially fewer side effects than current options, offering hope for improved vision and quality of life for patients.

What evidence suggests that this trial's treatments could be effective for keratoconus?

Research has shown that corneal collagen crosslinking, which uses riboflavin (a type of vitamin B) and UVA light, effectively treats keratoconus. This trial will compare two methods: continuous UVA and pulsed UVA. Both methods involve riboflavin administration and have proven safe in studies, helping control keratoconus progression. This treatment can slow or even halt the disease, crucial for younger individuals to prevent vision loss. Approximately 80% of cases experience stabilization or improvement in the cornea. The treatment strengthens the cornea, helping it maintain its shape and function. ^{4 6 7 8 9}

Who Is on the Research Team?

Peter S Hersh, MD

Principal Investigator

Cornea and Laser Eye Institute, Hersh Vision Group

Are You a Good Fit for This Trial?

Adults diagnosed with keratoconus or corneal ectasia following refractive surgery can join. They must have specific corneal steepening, be willing to follow the visit schedule, and not wear contact lenses for a week before screening. Pregnant women, those planning pregnancy, lactating individuals, or people with certain eye conditions or sensitivities are excluded.

Inclusion Criteria

I am 18 or older with a diagnosis of keratoconus or corneal ectasia.

Presence of central or inferior corneal steepening on the Pentacam map

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

Exclusion Criteria

I have noticeable scarring in the treated eye area.

Pregnancy (including plan to become pregnant) or lactation during the course of the study

I do not have any conditions like nystagmus that would prevent me from keeping my gaze steady during treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive corneal collagen crosslinking treatment with either continuous or pulsed UVA light

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in maximum keratometry (Kmax) and mean keratometry (meanK) post-treatment

6 months

Multiple visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Riboflavin Ophthalmic Solution

Trial Overview

The trial is testing an accelerated method of strengthening the cornea using riboflavin ophthalmic solution and UV-A light (either pulsed or continuous). The goal is to see if this speeds up oxygenation and improves treatment outcomes for patients with keratoconus or ectasia.

How Is the Trial Designed?

Group I: Continuous UVA Active Control 1 Intervention

Riboflavin administration one drop every two minutes with administration of 12mW/cm2 of continuous UVA light for 7.5 minute exposure time

Group II: Pulsed UVA Active Control 1 Intervention

Riboflavin administration one drop every two minutes with administration of 12mW/cm2 of pulsed UVA light for 15 minute exposure time

Riboflavin Ophthalmic Solution 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

Using dextran sulfate instead of the standard dextran (T-500) in riboflavin solutions during collagen cross-linking (CXL) for keratoconus led to severe complications, including persistent corneal epithelial defects and stromal haze, resulting in poor visual outcomes for all patients involved.

The study of 6 eyes from 4 male patients showed that these complications not only caused loss of vision but also complicated subsequent corneal transplants, highlighting the critical importance of using the correct dextran formulation in CXL procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistent Epithelial Defects and Corneal Opacity After Collagen Cross-Linking With Substitution of Dextran (T-500) With Dextran Sulfate in Compounded Topical Riboflavin. Höllhumer, R., Watson, S., Beckingsale, P.[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]

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]

Photooxidative crosslinking of corneal collagen using 0.1% riboflavin and UVA light at 370 nm is a safe and effective treatment for keratoconus, preventing disease progression.

In 80% of cases, this treatment resulted in a decrease in corneal curvature by about 2 diopters, leading to stabilization of the cornea and improved visual acuity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Collagen crosslinking with riboflavin and UVA-light in keratoconus]. Kohlhaas, M.[2021]

Corneal collagen cross-linking (CXL) with riboflavin significantly improved corneal topography and refractive outcomes in 66 patients with keratoconus over a one-year follow-up period, indicating its efficacy as a treatment.

Postoperative measurements showed a significant reduction in the mean spherical equivalent and improvements in corneal shape, demonstrating that CXL can effectively stabilize and enhance corneal structure in patients with progressive keratoconus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topographic corneal changes after collagen cross-linking in patients with corneal keratoconus. Razmjoo, H., Nasrollahi, AP., Salam, H., 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]

An 18-year-old boy developed bilateral viral keratitis after undergoing corneal collagen crosslinking for keratoconus, highlighting a rare complication associated with this procedure.

The condition was successfully treated with antiviral medication, leading to a good visual outcome, suggesting that prophylactic antiviral treatment may be beneficial for patients with a history of viral keratitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral viral keratitis following corneal collagen crosslinking for progressive keratoconus. Sitaula, S., Singh, SK., Gurung, A.[2020]

In a study of 38 eyes from 25 patients over 36 months, riboflavin UVA collagen crosslinking (CXL) treatment for keratoconus did not show significant changes in corneal topography indices or uncorrected visual acuity, indicating stability in corneal properties post-treatment.

While best-corrected visual acuity showed a slight improvement, it was not statistically significant, and importantly, no corneal thinning occurred, suggesting that CXL is a safe option for stabilizing keratoconus without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of corneal topography indices after collagen crosslinking for keratoconus. Hassan, Z., Szalai, E., Módis, L., et al.[2022]

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]

Citations

1.

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.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8232965/

A Prospective, Comparative, Clinical Study to Evaluate the ...

Both riboflavin formulations were found to be equally safe and effective in the management of progressive keratoconus in the present randomized comparison ...

3.

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 ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8004796/

Chemically-Boosted Corneal Cross-Linking for the Treatment ...

The purpose of this study was to evaluate the effectiveness and safety of a novel buffered riboflavin solution approved for corneal ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01972854

Safety and Efficacy of Corneal Collagen Cross-Linking in ...

The objectives of this study are to evaluate the safety and efficacy of corneal collagen cross-linking performed with VibeX (riboflavin ophthalmic solution) ...

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2016/203324s000lbl.pdf

NDA 203324/Original 2 Page 5 - 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 and effectiveness of riboflavin ophthalmic solution/UVA irradiation for performing corneal collagen cross-linking. These trials were sham-controlled ...

9.

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 combination with the KXL® System in corneal collagen cross-linking for the treatment of progressive ...