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Study on corneal collagen cross-linking under way at UPMC Eye Center
The main goal of the study is to halt keratoconus progression in young patients.
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Corneal collagen cross-linking has been used worldwide since Wollensak, Spoerl and Seiler’s paper in 2003. The basic concept of collagen cross-linking is to strengthen and stabilize a “weak” cornea by creating cross-links within and/or between the collagen fibrils.
Although some investigators feel the collagen fibrils are too far apart to actually be cross-linked, there is consensus that three ingredients are necessary to “stiffen” corneas: riboflavin, oxygen and ultraviolet light (UVA). Riboflavin acts as a photosensitizer in the presence of UVA, which results in the release of oxygen and riboflavin radicals. The end result is photo- polymerization with formation of collagen cross-links in the corneal stroma. After cross-linking, the corneal collagen fiber diameter is increased with a significant increase in corneal rigidity as well as an increased resistance to collagenase digestion. This latter feature makes cross-linking a possible therapy for corneal melting disorders.
The main use of corneal collagen cross-linking is to “strengthen” or “freeze” the cornea in patients with keratoconus in order to halt progression of the corneal ectasia. There is usually a slight improvement in best corrected visual acuity and an average of 2 D flattening of central keratometry.
Deepinder K. Dhaliwal
When performing cross-linking, the cornea is saturated with riboflavin either by first removing the epithelium or by using a transepithelial formulation and a longer soak time. After this, the riboflavin-soaked cornea is exposed to ultraviolet light. The original Dresden protocol created by Seiler’s group uses an ultraviolet light source with an irradiance of 3 mW/cm² for 30 minutes. An accelerated form of cross-linking by Avedro uses a higher irradiance of 30 mW/cm² for 4 minutes. Current U.S. Food and Drug Administration studies are under way using both technologies because cross-linking has not been yet approved by the FDA.
FDA cross-linking study
The UPMC Eye Center was chosen by Avedro as a site for its FDA study. We are currently enrolling patients.
Inclusion criteria are:
- Age of at least 12 years, male or female, of any race.
- Provide written informed consent and sign a HIPAA form. Patients who are under the age of 18 years will need to sign an assent form as well as have a parent or legal guardian sign an informed consent.
- Willingness and ability to comply with schedule for follow-up visits.
- For females capable of becoming pregnant, agree to have urine pregnancy testing performed before randomization of the study eye and before treatment of a fellow and/or crossover eye; must not be lactating; and must agree to use a medically acceptable form of birth control for at least 1 week before the randomization visit, 1 week before treatment of a fellow eye or crossover eye, and continue to use the method for 1 month after the last treatment.
- Topographic evidence of keratoconus with a diagnosis of mild, moderate or severe, defined as the following:
Mild keratoconus: axial topography consistent with keratoconus; flat Pentacam (Oculus) keratometry reading of 51 D or less.
Moderate keratoconus: axial topography consistent with keratoconus; flat Pentacam keratometry reading of 51.01 D or higher and 56 D or less or astigmatism of 8 D or higher.
Severe keratoconus: axial topography consistent with keratoconus with marked areas of steepening; flat Pentacam keratometry reading of 56.01 D or higher.
- Presence of central or inferior steepening on the Pentacam map.
- Have a maximum corneal curvature, as measured by Kmax, of 47 D or higher.
- BCVA of one letter or more and 80 letters or less on ETDRS chart.
- Contact lens wearers only: Removal of contact lenses is required for at least a 1-week period before the screening visits.
- Contact lens wearers only: Manifest refraction must be stable between two visits that occur at least 7 days apart. A stable refraction is one in which the manifest refraction spherical equivalent and the average K on the Pentacam taken at the first visit do not differ by more than 0.75 D from the respective measurements taken at the second exam.
Exclusion criteria are:
- Contraindications, sensitivity or known allergy to the use of the test articles or their components.
- If female, being pregnant, nursing or planning a pregnancy or having a positive urine pregnancy test before the randomization or treatment of either eye or during the course of the study.
- Eyes classified as normal, atypical normal or keratoconus suspect on the severity grading scheme.
- A history of corneal surgery or the insertion of Intacs (Addition Technology) in the eye to be treated.
- A history of limbal relaxing incisions in the eye to be treated.
- Corneal pachymetry that is less than 375 µm before epithelial debridement at the thinnest point measured by Pentacam in the eye to be treated.
- Eyes that are aphakic.
- Eyes that are pseudophakic and do not have a UV-blocking lens implanted.
- Eyes that have the maximum corneal curvature outside of the central 5-mm zone as measured by the Pentacam.
- Previous ocular condition (other than refractive error) in the eye to be treated that may predispose the eye for future complications. For example:
History of corneal disease (eg, herpes simplex, herpes zoster keratitis, corneal melt, corneal dystrophy), or clinically significant corneal scarring in the cross-linking treatment zone that is not related to keratoconus or, in the investigator’s opinion, will interfere with the cross-linking procedure.
- A history of delayed epithelial healing in the eye to be treated.
- Patients with nystagmus or any other condition that would prevent a steady gaze during the treatment or other diagnostic tests.
- Patients with a current condition that, in the investigator’s opinion, would interfere with or prolong epithelial healing.
- Taking vitamin C (ascorbic acid) supplements within 1 week of the cross-linking treatment.
- A history of corneal cross-linking treatment in the eye to be treated.
- Have used an investigational drug or device within 30 days of the study or be concurrently enrolled in another investigational drug or device trial within 30 days of the study.
- In addition, the investigator may exclude or discontinue any subject for any sound medical reason.
Additional trials and uses
Avedro is planning a future trial in which pulsed UVA light and supplemental oxygen will be utilized in order to increase the amount of collagen cross-linking in the cornea.
Additional therapeutic uses of cross-linking include treatment of post-LASIK ectasia, infectious keratitis that is unresponsive to traditional therapy and corneal melting disorders. LASIK Xtra is a refractive application of cross-linking used mainly after hyperopic LASIK in order to prevent regression of effect.
In summary, corneal collagen cross-linking is an exciting new technique that we are currently utilizing at the UPMC Eye Center in patients with keratoconus as part of a study. The main goal is to halt progression of keratectasia. Ideally, young patients who exhibit keratoconus progression will be treated early and therefore maintain adequate corneal thickness and curvature throughout their life. Additional applications are being studied in other parts of the world.
Visit UPMCPhysicianResources.com/Ocular to learn more about the use of corneal collagen cross-linking in clinical practice. You can also submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.
References:
Wollensak G, et al. J Cataract Refract Surg. 2003;doi:10.1016/S0886-3350(03)00407-3.
For more information:
Disclosure: Dhaliwal is an investigator for Avedro and AMO.