Effectiveness of customized corneal crosslinking versus standard corneal crosslinking in patients with progressive keratoconus

Keratoconus is a degenerative disorder of the cornea involving disruption and
loss of the native collagen network leading to severe thinning of the
epithelium and stroma. The disease is progressive resulting in a typical cone
shape of the cornea which causes myopia and irregular astigmatism impairing the
vision. Recent ultra-structural examinations show that the disease is regional
and does not affect the entire cornea in its early stage.

Keratoconus onsets during puberty and tends to gradually progress until the
mid-20s and 30s. Around the age of 40 the disease begins to stabilize, showing
hardly any progression in patients older than 45. With a prevalence of
approximately 265 cases per 100,000 individuals and an incidence of
approximately 13 cases per 100,000 in the Netherlands, the disorder is
relatively common. While the cause of keratoconus is not fully understood,
disease progression seems to be influenced by genetic and environmental
factors.

In 2003 Wollensak et al used corneal cross-linking (CXL) in humans to halt the
progression of keratoconus. During this procedure the cornea is soaked with
riboflavin, a photosensitizer, during 30 minutes. Hereafter a 9.0 mm diameter
Ultraviolet-A (UVA) beam radiates the cornea for 30 minutes with a fluence of 3
mW/cm2 resulting in a total energy of 5,4 J/cm2. This protocol is called the
Dresden protocol. Currently, accelerated versions of the Dresden protocol are
used in common practice. There are different accelerated protocols with
fluences of 9mW/cm2, 10mW/cm2 and 15 mW/cm2. The higher the fluence, the
shorter the treatment time, however according to the Bunsen-Roscoe reciprocity
law the total amount of energy stays the same. During the procedure oxygen
radicals are formed that interact with the surrounding molecules, leading to
the formation of new chemical bounds between the collagen fibrils (i.e. corneal
crosslinks). The final goal of the procedure is to cause the cornea to stiffen
and achieve flattening of the treated region.

For any disease treatment, it is imperative that the unaffected region of the
tissue is not unnecessarily treated by an intervention or drug application. To
minimalize the risk of damage to surrounding tissues it would be beneficial
that the UVA beam is restricted to the degenerated, keratoconic zone in the
patient cornea. This can be achieved by customizing the beam shape and size in
a way that only the degenerated zone is treated, i.e. by customized
cross-linking (cCXL). Recently published studies provide clinical evidence that
similar clinical outcomes (amount of corneal flattening) can be achieved when
only the cone is treated instead of the entire cornea. They also show the
potential benefits of cCXL, e.g. the treatment is patient-specific, a smaller
surface of the cornea is irradiated, lower incidence of corneal haze, a faster
reepithelialisation and a shorter procedure time. However, none of these
studies are randomized and study results are limited by using small sample
sizes. Therefore, we feel that there is a great need for a randomized
controlled trial with an appropriate design and sample size to confirm these
findings.

The objective of this project is to evaluate whether the effectiveness of
customized cross-linking (cCXL) is non-inferior to the standard cross-linking
protocol (sCXL).

a multicenter prospective randomized controlled non-inferiority interventional
clinical trial with a duration of 28 months.

In the standard corneal cross-linking protocol (sCXL) anesthetic drops are
applied on the cornea. The epithelium is debrided with alcohol over a region
with a diameter of 9.0 mm. Hereafter the cornea is soaked with 0.1%
riboflavin, saline, HPMC (VibeX RapidTM) 1 drop every 2 minutes during 10
minutes. After the application of riboflavin the cornea is irradiated with UVA
with a fluence of 10 mW/cm2 during 9 minutes with a diameter of 9.0 mm, this
gives a total energy of 5.4 J/cm2. The procedure is done with the Avedro Mosaic
CXL device (Avedro, Inc. Waltham, Massachusetts, United States). After the
procedure a bandage contact lens is placed.


In the customized corneal cross-linking protocol (cCXL) a patient-specific
treatment pattern, based on the patient*s Pentacam images, will be used to
treat the cornea.
The CXL pattern exists out of 3 circles and is centered on the cone. To
estimate the cone location a combination of the thinnest corneal point, maximum
anterior elevation and maximum posterior elevation is used. The average of
these 3 points is calculated and functions as the center for the treatment
pattern. The treatment pattern itself are 3 concentric circles. The diameter of
the smallest circle is 4 mm, of the middle circle 5.25 mm and of the biggest
circle is 6 mm. Each circle receives a different amount of energy, which
gradually decreases with increasing circle size. The smallest circle receives
the highest amount of energy, 10 J/cm2, this is equal to a fluence of 10 mW/cm2
for 16.7 minutes. The middle circle receives 7.2 J/cm2 and the biggest circles
receives 5.4 J/cm2.

First, anesthetic drops are applied on the cornea. The patient-specific
treatment pattern will be projected onto the cornea with the Avedro Mosaic
centered on the cone location. The pattern is marked on the cornea and the
epithelium is debrided with alcohol within the marked zone. Then the cornea is
soaked with 0.1% riboflavin, saline, HPMC (VibeX RapidTM) 1 drop every 2
minutes during 10 minutes. The procedure is done with the Avedro Mosaic CXL
device (Avedro, Inc. Waltham, Massachusetts, United States). After the
procedure a bandage contact lens is placed.

The study process is the same as the regular care process concerning follow-up
visits and examinations.
The examinations are not invasive and only take up a limited amount of time.
When patients participate in the study they are asked to fill in a few
questionnaires during different follow-up visits. The questionnaires ask about
quality of life and quality of vision. Filling out the questionnaires takes
about 20 minutes. Patients are asked to indicate the ocular pain they
experience the first 4 days after CXL on a Visual Annalogue Scale (VAS).
The difference between the burden of participating in the study and the burden
of regular care is minimal.