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Corneal Collagen Cross-linking Study

Royal Victorian Eye and Ear Hospital (RVEEH)
Centre for Eye Research Australia (CERA)

Trial Update June 2011
The Centre for Eye Research Australia (CERA) in Melbourne has provided the Association with an update on its corneal collagen crosslinking trial. Started in 2006, the CERA trial was the world's first randomized clinical trial of corneal crosslinking and is being followed closely by corneal surgeons and keratoconus patients in Australia and overseas.

Four Year Findings
Data ana
lysis including up to 4-year findings were presented at the International Congress of Collagen Crosslinking in Milan in January 2011
. Data analysis including up to 4 year findings were presented at the 6th International Congress of Collagen Cross Linking in Milan in January 2011.

At the time of the last interim analysis, nine treated patients and ten patients from the control group had completed their four year follow-up. While there are considerable individual differences in the initial post-operative period, follow-up at the 4 year mark indicates that patients who receive CXL remain stable or show a slight improvement in either vision, corneal steepness, or both.

Participants in the control group on average experienced a slight worsening of their condition. In cases where marked progression was noted, patients in the control group were offered the treatment on compassionate grounds. To date, 13 patients have received CXL for this reason.

It should be emphasized that this trial only involves patients with progressive keratoconus who are 16 years or older. While there is increasing interest in CXL for younger patients, there is currently only limited research data available to support this. Therefore any decision to treat a patient under 16 years of age with CXL would need to be carefully considered and can only be made on an individual basis.

The conference highlighted the high level of interest internationally of the Australian trial. During the congress, two major variations of the current recommended protocol were the subject of lively discussion. These were:
1) the potential to achieve effective CXL treatment without removing the corneal epithelium (outer skin of the cornea) and 2) variations in the treatment parameters intended to achieve comparable results with shorter treatment times.

While these amendments would be equally appealing to both people undergoing the treatment and clinicians performing CXL, doubts were expressed about the efficacy of the currently trialed ‘epithelium on’ options. Although the concept of a shorter treatment time might hold great future potential, the majority of Congress delegates agreed that there is a need for thorough scientific evaluation of any treatment variation and that a formally structured protocol should be developed.

The full update can be downloaded here.

Interested in becoming a study participant?
Patients who are interested in participating in the ‘thin cornea’ pilot study, keratectasia pilot, or in being involved in future trials are advised to contact their eye care specialist or Tony Wu (Trial Coordinator) on 03 9929 8618 or tonyn@unimelb.edu.au.

Funding to continue these important trials is still required. If you would like to donate, please contact Fiona Slocombe (CERA Fundraising Administrator) on 03 9929 8426 or fiona.slocombe@unimelb.edu.au.


Trial Update July 2009

Key Findings

  • Although results varied in the first 3-6 months, after 12 months all patients who received the crosslinking treatment showed stabilization in their keratoconus at their pre-treatment level.

  • Some patients even experienced a mild flattening in their cornea.

  • The full update can be downloaded in pdf format here.

 

Trial Update December 2008
A previous update on the corneal collagen crosslinking study can be found on the RVEEH website here

 

Details of the RVEEH Study

Disclaimer: This FAQ bulletin below has been posted by Keratoconus Australia in the interests of public information. Keratoconus Australia has relied on information provided by the trial conveners in preparing this FAQ bulletin. Keratoconus Australia and its officers cannot be held responsible for any claims about the treatment, the trial, its risks and outcomes. Nor will it accept responsibility for inaccuracies or misunderstandings arising from this bulletin. Patients interested in the trial are strongly advised to make their own inquiries about this treatment, the trial and its suitability and risks for them.

Keratoconus Australia supports research into treatments for keratoconus and its effects on vision. As part of its commitment to research in this field, the Association is providing assistance to the trial organizers. However as a patient support group, we are not qualified to make judgments about the safety or usefulness of experimental treatments like the collagen crosslinking treatment for keratoconus. Nor do we stand to make any financial gain from the trial.

Many people have been asking us about the new treatment for keratoconus publicized first in April 2006. There has been much confusion about the nature of the treatment, who it can help and when it will be available.

This information has been prepared to explain the new collagen cross-linking treatment being trialed at Melbourne’s Royal Victorian Eye & Ear Hospital.

A seminar was held on 30 May 2006 in Melbourne to provide an opportunity for keratoconus patients and their families to hear more about the treatment, the trial and to ask questions about how this could affect them. The video of this seminar is now available.

Trial Update April 2007
by Dr Christine Wittig, Research Fellow CERA

In October 2006, a second site joined the trial. Professor Lawrie Hirst is the leading investigator in Queensland and can be contacted at the Queensland Eye Institute in Brisbane on 07 3010 3360 (phone) or 07 3010 3390 (fax).

Currently, there are 35 patients (48 eyes) enrolled in the trial – 27 patients (38 eyes) at the RVEEH and 8 patients (10 eyes) at the Queensland Eye Institute in Brisbane. The early results are promising, suggesting a treatment effect at 3 months. It is important that the trial continues to confirm these early trends and confirm that the effect is maintained.

Until recently, involvement in the trial has been limited to patients with a cornea thicker than 400 microns. However, many patients with progressive keratoconus have corneas thinner than this threshold. In order to allow these patients to participate in the trial, the procedure has been modified in a way causes the cornea to swell (thicken) temporarily for the duration of the treatment (approximately 45 minutes). Although worldwide the number of eyes treated in this way remains small, early results indicate that this strategy provides a similar level of protection of the deeper ocular tissues. In February 2007, the RVEEH Human Research Ethics Committee approved this amendment to the original protocol which allows eyes with a corneal thickness of at least 330 microns to be enrolled in the trial.

Funding is now being sought to continue recruitment for this study for at least the next six months. Anyone in a position to assist in the financial support of this project may do so through and every support is greatly appreciated. For details please contact the Fundraising Manager at the Centre for Eye Research Australia, on (phone) 03 9929 8360 , (fax) 03 9662 8423 or Email: cera-info@unimelb.edu.au  

 

FREQUENTLY ASKED QUESTIONS

 What is keratoconus?

The cornea is the clear window on the front of the eye. It provides the majority of the focussing power of the eye. Keratoconus is a common bilateral corneal condition, occurring in more than 1 in 2000 people. It is characterised by progressive corneal thinning and stretching which gradually progresses in both eyes allowing the corneas to bulge forward and adopt an irregular cone shape. As a result, the eye develops astigmatism and the vision may become severely blurred.

The condition typically starts in adolescence and early adulthood. Initial management is with glasses or rigid contact lenses. Replacement of the central cornea by corneal transplantation surgery becomes necessary in a minority of affected individuals when vision can no longer be improved with glasses or contact lenses.

 

What is collagen cross-linking?

Although current treatments can improve vision in keratoconus, they do not treat the underlying cause of the corneal weakness and distortion. They do not stop the progression of keratoconus.

A new technique of collagen cross-linking using the photosensitizer riboflavin (vitamin B2) and ultraviolet light (UVA) has been developed in Europe. In extensive experimental studies in animal eyes (including biomechanical stress & strain measurements) researchers have demonstrated a significant increase in corneal rigidity or stiffness after collagen cross-linking using this riboflavin/UVA treatment.

A pilot clinical study in humans evaluated the effect of the new cross-linking method in patients with keratoconus and showed that, in all treated eyes, progression of the condition was halted. To date there are over 100 patients with more than 2 years follow-up after cross-linking treatment and some eyes have been followed for 5 years with encouraging results.

 

How is the treatment done?

The treatment involves removing the skin (epithelium) from the surface of the cornea and then applying Riboflavin eye drops. The eye is then exposed to UVA light for 30 minutes. After the treatment, an eye-pad is worn for 1-3 days and antibiotic ointment is applied to the treated eye four times a day until the surface of the eye has healed.

 

Who can benefit from this treatment?

It is important to understand that collagen cross-linking treatment is not a cure for keratoconus. Rather, it aims to slow or even halt the progression of the condition. After the treatment, it is expected that it will continue to be necessary to wear spectacles or contact lenses (although a change in the prescription may be required). However, it is hoped that the treatment will prevent further deterioration in vision and the need for corneal transplantation.

A person whose keratoconus is already so bad that it cannot be corrected by contact lenses is unlikely to gain any benefit from this treatment. In this situation a corneal transplant is usually required.

Initially the treatment would be offered only to patients in whom there is clear evidence of progression of their keratoconus.

 

When would this treatment become more widely available to other keratoconus patients?

Should the treatment prove safe and effective, it is likely that it will be made more widely available. It is possible that other centers will offer this treatment before the trial is concluded.

 

What is the trial being conducted at the RVEEH?

The trial is a randomized control trial designed to test the hypothesis that Riboflavin/UVA treatment may be useful in maintaining and improving corneal rigidity in keratoconus, and may retard or even stop progression of the disease.

The trial aims to:

1.  Evaluate the clinical usefulness and efficacy of Riboflavin/UVA treatment in those with progressive keratoconus.

2.  Confirm the safety profile of this treatment.

Approximately 100 volunteers will participate in the trial. Approximately 50% of the eyes that qualify will be randomly allocated to receive the treatment; the other 50% will act as the control group and will not receive the treatment. Subjects in both groups will undergo regular detailed clinical examinations over the course of the trial.

The results will be analyzed at regular intervals during the course of the study. If there is a significant effect observed in treated patients (relative to the control group), those patients in the control group will also be offered the treatment (free of charge). The trial will be continued for up to 5 years in order to gather valuable long-term data.

 

Am I eligible to participate in the trial?

To be eligible to participate in the trial, you will need to meet two essential criteria:

1.  The diagnosis of keratoconus must be confirmed based on clinical examination findings and corneal topography (mapping), and

2.  There must be evidence of progression of the keratoconus occurring over the last 12 months. This would be determined in conjunction with the treating optometrist and/or ophthalmologist based on changes in contact lens prescription, spectacle prescription and measurements of corneal shape (keratometry or computerized corneal mapping).

 

You will NOT be eligible to participate in the trial if any of the following apply:

∑        You are aged less than 16 or older than 50 years

∑        You are pregnant or breastfeeding

∑        There is a past history of Herpes Simplex Keratitis or corneal surgery

∑        Your cornea is too thin (less than 330 microns)

∑        Other corneal disease or scarring is present

∑        There is a history of chemical burns to the cornea or healing problems.

∑        There is a known allergy to Riboflavin

 

Please note that patients MUST be able and willing to attend regular examinations at the Royal Victorian Eye & Ear Hospital in East Melbourne. There could be as many as 8 visits during the first 12 months and annual checkups thereafter for up to five years.

Patients who have had a corneal transplant in one eye may be able to participate if their un-operated eye satisfies these requirements. Those who have had transplants in BOTH eyes will not be able to take part in the study. 

 

What are the risks?

There are a number of potential risks associated with this treatment although very few complications have been reported so far.

Ultraviolet light is potentially harmful to the eye and some damage does occur to the cells in the front part of the cornea where the treatment has its effect. However, the dose used is designed to prevent observable damage to the cells that line the back of the cornea or the other structures within the eye. No lens opacities (cataracts) have been attributed to this treatment in European trials.

The treatment involves the scraping away of the outer layer (skin or epithelium) of the cornea. There is therefore a risk that the surface of the cornea will be slow or fail to heal.

Infection may occur which could lead to the development of corneal scarring. Antibiotics are routinely used to prevent this complication. Corneal scarring might necessitate further surgical procedures (including corneal transplantation).

Other lesser but more common risks include:

∑        Inability to wear contact lenses for several weeks after the treatment

∑        Changes in the shape of the cornea necessitating a refitting of a contact lens or a change in the spectacle correction.

As is the case with any experimental treatment, there may also be long-term risks that have not yet been identified.

The increased corneal rigidity induced by exposure to UVA and riboflavin may wear off over time and further periodic treatments may be required, raising the possibility of other side effects from repeat doses of the treatment.

 

Who will conduct the trial?

The trial is being conducted by the Corneal Unit of the RVEEH in Melbourne led by Dr Grant Snibson. Dr Christine Wittig, the principal researcher, is a German doctor who participated in the early trials of collagen cross-linking at the Dresden Hospital, Germany.

The study has been approved by the Hospital’s Human Research Ethics Committee.

 

Will I be paid for participating in the trial?

No.

No payments will be made to subjects for their participation in the trial or to cover any expenses related to their attendance for examinations. All treatments and examinations related to the trial will be provided free of charge to participants.

 

If I can’t participate in the trial, how can I assist?

Funding is still required for the study and contributions can be made by contacting the Centre for Eye Research Australia (CERA)

Phone :03 9929 8360   Fax: 03 9662 3859  Email: cera-info@unimelb.edu.au

 

How can I get more information about participating in this trial and the collagen cross-linking treatment?

If you have evidence from your optometrist that you may be a suitable candidate for this trial (see above), you can contact the trial organizers by faxing reports from your optometrist on the progression of your keratoconus and your corneal thickness to 03 9662 3859 or emailing the trial organizers .

Keratoconus Australia and the trial organizers held a public seminar on May 30, 2006 in Melbourne to provide an opportunity for keratoconus patients and their families to hear more about this treatment, its benefits and risks and the trial itself. A video of the seminar is now available. Go to Events for further details.

 

This information bulletin has been prepared by Keratoconus Australia in conjunction with Dr. Christine Wittig Research Fellow, Centre for Eye Research Australia.