The U.S. Food and Drug Administration (FDA) recently permitted the start of three clinical trials in the United States to evaluate the safety and effectiveness of riboflavin/UVA light corneal collagen cross-linking (CXL) in patients with progressive keratoconus or corneal ectasia after previous refractive surgery.
The first patients were treated in the United States by Dr. R. Doyle Stulting, MD, PhD, at Emory University as part of a physician-sponsored study in early January, 2008. “We are extremely excited to begin clinical trials on crosslinking. It may be a way to cure a disease that has no current treatment and accounts for 15% of the corneal transplants performed in the United States.” said Dr Stulting, Medical Director for the cross-linking program and Principal Investigator for the physician-sponsored IND.
|Figure 1 shows cornea layers beforecross-linking.||Figure 2 indicates increased cross-linking after treatment.|
The two multicenter studies, one for progressive keratoconus and the other for ectasia, are sponsored by the Swiss-based company, Peschke Meditrade GmbH. At present there are ten sites in the US (see side bar).
All studies are randomized, controlled clinical trials to determine the safety and effectiveness of the UV-X™ Illumination System for performing corneal collagen cross-linking (CXL) in eyes with corneal ectasia or progressive keratoconus. Each trial is expected to include 160 patients with keratoconus and 160 patients with corneal ectasia. The studies will compare the effect of Riboflavin/UVA light (CXL treatment group) to that of Riboflavin alone.
In the US studies, corneal collagen cross-linking is performed by removing the corneal epithelium (“epi-off”) and applying riboflavin drops to the eye. After the cornea is saturated with the riboflavin, the eye is exposed to the ultraviolet (UVA) light. The UVA light interacts with the riboflavin, producing reactive oxygen molecules that cause the formation of chemical bonds between and within the corneal collagen fibrils, making them stiffer.
At 3 to 6 months, subjects whose eye(s) have not developed any contraindications for performing the CXL treatment will be given the option of having CXL performed on their untreated fellow eyes and eyes that were randomized to the control group. All eyes are followed for 12 months after the CXL procedure.
Clinical applications of corneal collagen cross-linking include treatment of conditions distinguished by alterations in corneal structure, such as post-LASIK ectasia, progressive keratoconus, and pellucid marginal degeneration (PMD). (However, PMD is not included in this study).
Keratoconus is a naturally occurring ocular condition characterized by progressive thinning and steepening of the central cornea, resulting in increasing myopia, irregular astigmatism, and eventual loss of best spectacle-corrected visual acuity. Rigid contact lenses can be used to improve visual acuity in many patients, but keratoconus frequently progresses to the point that corneal transplantation is required to restore useful vision. Keratoconus may recur following corneal transplantation and require further transplant surgery.
Together, keratoconus and post-refractive corneal ectasia are the second most frequent indication for corneal transplantation, accounting for about 15% of the corneal transplants performed in the United States. Corneal transplantation has inherent risks that could result in permanent loss of vision and significantly impact the patient’s quality of life during the surgical recovery phase, with lost work time and often permanent changes in lifestyle. Any modality, such as corneal collagen cross-linking, that can delay or prevent corneal transplantation in patients with these conditions is of great benefit.
At this time there is no medical therapy available in the United States to control the progression of keratoconus or corneal ectasia following refractive surgery. Corneal collagen cross-linking using UVA light with riboflavin photosensitizer to strengthen corneal tissue has shown promising success internationally in stabilizing corneal curvature and slowing or stopping the progression of keratoconus and post-refractive ectasia.
Currently available published data, unpublished data, and personal observations by current international investigators and those surgeons in the U.S. who are following patients who have traveled internationally to have the procedure performed make a convincing argument that collagen cross-linking is significantly safer than corneal transplantation. Based on the available data, corneal collagen cross-linking offers a treatment for a disease that currently has no real treatment except corneal transplantation.
To date, the only adverse event reported after cross-linking has been corneal edema in an eye with a pretreatment corneal thickness of less than 400 microns, presumably caused by UV damage to the corneal endothelium. Subsequent experiments led to the conservative recommendation that corneas not be treated with UVA/riboflavin unless they are thicker than 400 microns after epithelial debridement. This is the protocol used in the US studies.
In other studies, nerve regeneration was observed at 1 month and nerve fiber recolonization was complete at 6 months with restoration of corneal sensitivity. No changes were observed in the peripheral untreated area at any time.
Riboflavin, also known as Vitamin B2, is a naturally occurring photosensitizer. It is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), two coenzymes that are crucial for the metabolism of carbohydrates, fats and proteins into energy. Riboflavin is an essential constituent of all living cells. It is water soluble and only a trace amount is found in the human body. Riboflavin is non-toxic and it is used as a coloring agent in food and pharmaceuticals. No adverse effects have been associated with high intakes of riboflavin from food or supplements.
The potential toxicity of UVA light and riboflavin on keratocytes and the corneal endothelium have been evaluated in a series of laboratory experiments, in which porcine cell cultures were exposed to riboflavin alone, UVA light alone, and riboflavin in combination with UVA light. In each experiment, riboflavin alone was non-toxic; UVA light alone showed a cytotoxic effect, and, riboflavin/UVA light exhibited a cytotoxic effect at an exposure level that was ~10-fold lower than UVA light alone. Endothelial cell damage and keratocyte toxicity is believed to be due to oxidative damage caused by the oxygen reactive free radicals (singlet oxygen, superoxide anion, hydrogen peroxide) that are generated when riboflavin is irradiated by the UV light.
The lower cytotoxic thresholds observed for the UVA/riboflavin combination in the keratocyte and endothelial cell toxicity studies is consistent with the increase in UVA absorption in the anterior cornea in the presence of riboflavin. For example, 94% of incident UVA light is absorbed in the anterior 400 microns of the corneal stroma in the presence of riboflavin, as depicted in the graph below, whereas only 32% is absorbed within that depth in the absence of riboflavin
Anterior stromal UVA absorption with riboflavin
The CXL procedure is under investigation in the U.S., but results from international clinical trials indicate that CXL treatments halt the progression of keratoconus and ectasia by improving the biomechanical stability of the cornea, resulting in corneal flattening and improved vision. The effects appear to be long-term, with some patients in the European studies having been followed for up to 8 years after the treatments.
“Internal data and personal experience with my own patients who have been treated in Europe lead me to believe that CXL is safe and effective for the treatment of keratoconus and ectasia after LASIK” reported Dr Stulting.
More information on these studies including specific inclusion and exclusion criteria can be found on the federal government’s clinical trials listing service website.