Patron: Her Majesty The Queen
City Road
London
EC1V 2PD
Chairman
Sir Thomas Boyd-Carpenter
Chief Executive
I.A.J Balmer
Tel 020 7253 3411
Minicom 020 7566 2279
Patient Information Sheet
Collagen Cross-linking with Riboflavin in a Hypotonic Solution,
with UV light,
on corneas less than 400 microns thick: an exploratory study.
A study of the clinical results of a new method of potentially stabilising the cornea, and possibly
improving the unaided vision, of patients with keratoconus.
You are being invited to take part in a research study. Before you decide, it is important for you to
understand why the research is being done and what it will involve. Please take time to read the
following information carefully and discuss it with friends, relatives and your GP if you wish. Ask
us if there is anything that is not clear or if you would like more information. Take time to decide
whether or not you wish to take part.
Study purpose
You have a condition called keratoconus that has affected your cornea (the front focusing lens of
the eye). In keratoconus the progressive change in shape of the cornea leads to visual
deterioration. Usually this is treated initially with spectacles, or gas permeable or scleral contact
lenses, but this does not stop the possibly progressive nature of the condition, and in about 20% of
patients eventually the cornea may need to be removed and replaced by a corneal transplant.
Although corneal transplantation is often successful, it is only generally performed once the
keratoconus has progressed to an advanced state, and following corneal grafting it may take
between 12 and 18 months to provide an improvement in vision. There is also a lifelong risk that a
corneal graft may be rejected by your body.
This research study sets out to evaluate a new technique called Collagen Cross-linking with
Riboflavin in a Hypotonic Solution, which aims to treat keratoconus at an earlier stage, hopefully
halting possible progression, and potentially improving the unaided vision. This research is being
conducted by surgeons at Moorfields Eye Hospital as part of a prospective clinical trial.
Studies carried out in Europe over the past few years on several hundred patients with corneas
greater than 400 microns thick, have shown that cross-linking treatment in such cases prevents
progression of keratoconus, and in some cases has given some degree of improvement in the
vision. Studies of cross-linking in patients with corneas thinner than 400 microns are currently
being carried elsewhere in Europe, but no results have been published yet. These studies have yet
to demonstrate that the technique is effective or reliable in thin corneas, or that there is no damage
incurred to the corneal endothelial cells.
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What is riboflavin?
Riboflavin is a vitamin (B2) which occurs naturally in many common foods (eg; milk, cheese, leafy
green vegetables). In this study, riboflavin is applied to the surface of the eye in the form of eye
drops, and is absorbed into the cornea and into the aqueous fluid of the eye. It has two effects
during the UV treatment: one is to help the chemical reaction that cross-links the collagen fibres in
the cornea, increasing their strength. The other is to absorb any UV light that penetrates through
the cornea, and in so doing, prevent damage to the internal structures of the eye such as the lens
and retina, from the effects of the UV light.
The total dose of riboflavin applied to the eye will be less than half the amount that is found in a
single pill of a typical over-the-counter Vitamin B2 supplement. The eye drops are made with
purified water, which is absorbed into the corneal stroma, making it waterlogged and thicker. In
this way your cornea is temporarily increased to the level of thickness normally required for
conventional cross-linking. Currently there is no licensed pharmaceutical preparation of riboflavin
eye drops, but the drops used in this study are supplied from the manufacturer as a CE marked
medical device.
Why have I been chosen for this study?
You have been invited to participate in this study because you have keratoconus. This is a condition in
which the cornea has become thin, weak and mechanically unstable, resulting in an irregular corneal
contour.
Until recently, the only way to surgically correct keratoconus was to carry out a conventional corneal
graft, in which the central part of the patient’s cornea is removed, and replaced with a corneal
transplant. Collagen cross-linking is different, as your cornea is not removed, and no corneal graft is
necessary. This pilot cross-linking with hypotonic riboflavin study is expected to look at the effects of
the treatment on 5 eyes of patients like yourself who have a keratoconus.
Do I have to take part?
It is up to you to decide whether or not to take part. If you do decide to take part you will be given
this information sheet to keep and be asked to sign a consent form. If you decide to take part you
are still free to withdraw at any time and without giving a reason. This will not affect the standard
of care you receive.
What will happen to me if I take part?
To determine whether you are eligible to be admitted to this study you will have to have assessment of
your corneal endothelial cell layer by specular microscopy. This is a simple examination using special
equipment to examine the corneal endothelial cells under high magnification. Your endothelial cell
density will need to be greater than 2400 cells/mm2 for you to be allowed to proceed into the study.
Only patients with a normal endothelial cell density are being selected in order to minimise the risk to
corneal function if endothelial damage should occur as a consequence of the treatment.
Only one eye is treated at a time. If you wish to have both eyes treated you will have to wait a
minimum of 3 months between having the two eyes treated.
If you choose to enter this study then the surgery will be scheduled on a routine basis that corresponds
to our normal surgical schedule. The surgery will be performed under local anaesthesia with
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anaesthetic eye drops. The surgery involves removal of the superficial cell layer of the cornea
(epithelium), and then riboflavin eye drops will be put into the eye frequently over a period of up to 30
minutes, until your surgeon finds that a sufficient degree of corneal oedema, and riboflavin saturation,
has been obtained. At that point the ultra-violet light will be directed onto your cornea for 30 minutes
to produce collagen cross-linking. Cross-links are small bridges between the fibres in your cornea,
which strengthen the cornea.
The riboflavin eye drops are instilled at 5 minute intervals throughout the period of UV illumination.
After the procedure is finished a special bandage soft contact lens is placed on the surface of the
cornea, and antibiotic, steroid, and dilating drops are applied.
The next morning your eye will be examined and you will continue on antibiotic and steroid drops to
prevent infection and to help with healing. The first visit after surgery will only take about 15 to 30
minutes. Visits after that time will require further testing of your vision and of the cornea and will take
approximately 45 minutes to an hour. You will have a visit to the clinic 4 or 5 days after the procedure
to check on the healing of the corneal surface (epithelium). The bandage contact lens may be removed
at this time. Further follow-up appointments at one month, and three months after surgery will be
arranged for the study. We will of course see you at any time that you have any concerns, questions or
problems after your surgery, but these visits are the ones that are required by the study.
The tests that you will have performed are a visual acuity test, a check for glasses, examination with
the standard clinic microscope, and measurements of your cornea with various optical instruments,
which record light reflections from the cornea. None of these tests is difficult or uncomfortable for
you.
What do I have to do?
It would be normal to take a week or two off work to facilitate the frequent administration of drops and
allow time to recover from the mild gritty/watery discomfort which is common after surgery. You
should not go swimming for one week after surgery. You should also adhere to the regime for drop
treatment specified by your surgeon. Otherwise there are no special restrictions on activity.
What are the alternative treatments?
Alternative treatments for keratoconus are either to wear spectacles, rigid (gas permeable) or
scleral contact lenses, or to have corneal surgery such as Intacs implants, or to have a conventional
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deep anterior lamellar or a full-thickness corneal transplant. Following cross-linking surgery, the
eye drop treatment, and the number of clinic visits are similar or less to that required after a corneal
graft operation.
What are the possible risks of taking part?
The risks and discomforts of cross-linking treatment are as follows:
1. In the unlikely event that your cornea cannot be made to swell sufficiently such that the
thickness of the stroma (without the epithelium) reaches a minimum of 350 microns, then we
will not be able to proceed to the cross-linking, and the treatment will have to be abandoned.
2. The surface of the cornea (epithelium) is removed prior to application of the riboflavin eye
drops. Until the epithelium heals over, the eye may be quite sore. A bandage contact lens will
be placed onto the cornea after the procedure to make the eye more comfortable, and antibiotic
and steroid eye drops will need to be applied regularly. You may also need to take some pain
killers like paracetamol for a few days. Some patients find the eye sensitive to light for some
weeks after the treatment. Post-operatively there will be inflammation, and this could possibly
lead to sub-epithelial scarring, with impairment of vision.
3. An infection of the cornea may occur in around 1 in 1000 patients.
4. Ultraviolet light is potentially damaging to cells. Studies have shown that the cells within the
cornea called keratocytes are mostly destroyed by the treatment in the central area of the
cornea, but they are then replaced by healthy cells within a few months. Theoretically the inner
lining cells of the cornea (endothelium) could also be damaged if your cornea were too thin.
The endothelial cells do not have any regenerative capacity, so if there was extensive
endothelial cell damage the cornea could fail and become opaque, and a corneal transplant
would be required. For this reason we can only proceed with this treatment when the cornea
has increased sufficiently in thickness due to the water-logging effect of the hypotonic
riboflavin drops. Ultraviolet light may also potentially damage retinal cells, but virtually all the
ultra-violet light is absorbed by the riboflavin in the cornea, so the UV light level reaching the
retina should be well within recommended safe limits.
5. UV light is considered a factor in the causation of cataract (opacity in the lens of the eye).
However in the presence of the riboflavin, the amount of UV light actually reaching the lens of
the eye should be reduced to levels lower than that encountered under normal environmental
conditions, so should not be a problem. No cases of cataract caused by cross-linking treatment
have been described so far.
6. Although conventional cross-linking treatment has been shown to stabilise keratoconus in
patients with corneal thickness greater than 400 microns, it does not necessarily follow that a
similar treatment to a thinner cornea will have the same beneficial effect. The temporary
abnormal swelling induced by this treatment may stop the treatment from being effective in
strengthening the cornea, and may cause damage or lead to scarring.
7. Your keratoconus might progress in the future. In this case cross-linking treatment could
potentially be repeated, or a conventional corneal graft operation could be performed.
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Although we have tried to list all possible risks associated with this study, there may be others that we
are not yet aware of.
What are the possible benefits of taking part?
There are potential direct benefits to you as a patient involved in this study; however, there are no
guaranteed benefits. Information gained in this study should help to guide the future treatment of
patients similar to you.
1) The operation is quicker and simpler than conventional corneal graft surgery, and thus can
readily be performed under a local anaesthetic.
2) The speed of visual recovery following cross-linking treatment should be greater than
following a conventional graft.
3) Cross-linking could stabilise, and may even improve your vision.
4) The procedure could prevent progression of your keratoconus.
5) If your refraction is stabilised, this may open up the possibility of longer-term refractive
correction by other surgical means such as lens implants.
If this study demonstrates beneficial results of cross-linking treatment with hypotonic riboflavin, then
patients in the future with similar conditions will benefit from this study.
What if new information becomes available?
Sometimes during the course of a research project, new information becomes available about the
treatment that is being studied. If this happens, your research doctor will tell you about it and
discuss with you whether you want to continue in the study. If you decide to withdraw, your
research doctor will make arrangements for your care to continue. If you decide to continue in the
study you will be asked to sign an updated consent form. Also, on receiving new information your
research doctor might consider it to be in your best interests to withdraw you from the study.
He/she will explain the reasons and arrange for your care to continue.
What if something goes wrong?
If taking part in this research project harms you, there are no special compensation arrangements.
If you are harmed due to someone’s negligence, then you may have grounds for a legal action but
you may have to pay for it. Regardless of this, if you wish to complain about any aspect of the way
you have been approached or treated during the course of this study, the normal National Health
Service complaints mechanisms may be available to you.
Confidentiality
All information that is collected about you during the course of the research will be kept strictly
confidential. Any information about you which leaves the hospital/surgery will have your name
and address removed so that you cannot be recognised from it. Your surgery may be recorded on a
video camera for teaching purposes and for presentation of the research. Your eyes may also be
photographed before and after the surgery. These pictures will be taken in a close-up view that
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should not allow you to be recognisable when they are presented. Information will be archived for
the study on computers. This information will be anonymised and care will be taken to ensure that
only those responsible for your care in the study will have access to the data collected.
Where will results from the study be presented?
Results from the study will be presented in medical journals and at research meetings.
Who has reviewed the research study?
The study has been reviewed internally by the Moorfields Research Ethics Committee.
Contact for Further Information
When you reach a decision about participating in this study, or if you have further questions, please
contact the study co-ordinator:
Ms Suzanne Cabral
Research and Development
Moorfields Eye Hospital
London EC1V 2PD
Telephone: 020 7566 2036
Email: [email protected]
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