Efficacy of Customized Corneal Cross-linking vs. Standard Corneal Cross-linking (C-CROSS)

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Maastricht University Medical Centre (MUMC)






Procedure: Standard crosslinking
Procedure: Customized crosslinking

Study type


Funder types




Details and patient eligibility


The standard or Dresden protocol was established in 2003 and treats the entire cornea. However, recent ultra-structural research showed that keratoconus is localized. Therefore, treating only the affected zone and minimalizing the risk of damaging surrounding tissues would be beneficial. The objective of this study is to evaluate whether the effectiveness of customized cross-linking (cCXL) is non-inferior to standard accelerated cross-linking (sCXL) in terms of flattening of the cornea and halting keratoconus progression.

Full description

In 2003 Wollensak et al used corneal cross-linking (CXL) in humans to halt the progression of keratoconus. During the procedure the top layer of the cornea, the epithelium, is debrided. Then the cornea is soaked with riboflavin, a photosensitizer. 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 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 affected, keratoconic zone in the patient's 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 aim of this study is to investigate if cCXL is non-inferior to sCXL (10 mW/cm2) in terms of flattening of the corneal surface and halting the disease progression.


124 estimated patients




16 to 45 years old


No Healthy Volunteers

Inclusion criteria

Progressive keratoconus based on an increase of maximum keratometry (Kmax) of 1 diopter (D) over a time period of 12 months

Exclusion criteria

  • Corneal scarring
  • Corneal disease other than keratoconus
  • History of corneal surgery (e.g. refractive surgery, corneal transplantation, intracorneal ring segments)
  • Patient unwilling or unable to give informed consent, unwilling to accept randomization or inability to complete follow-up (e.g. hospital visits) or comply with study procedures
  • Insufficient corneal thickness including epithelium < 375 µm
  • Pregnancy
  • Among patients in whom both eyes are eligible only the first eye which is undergoing corneal cross-linking is enrolled in the study
  • Participation in another clinical study

Trial design

Primary purpose




Interventional model

Parallel Assignment


Single Blind

124 participants in 2 patient groups

Customized crosslinking
Active Comparator group
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 concentric 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 epithelium is debrided with alcohol within the marked zone. After the application of riboflavin each circle receives a different amount of energy, which gradually decreases with increasing circle size. The procedure is done with the Avedro Mosaic CXL device (Avedro, Inc. Waltham, Massachusetts, United States).
Procedure: Customized crosslinking
Standard crosslinking
Active Comparator group
In the standard corneal cross-linking protocol (sCXL) the epithelium is debrided with alcohol over a region with a diameter of 9.0 mm. 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, resulting in a total energy of 5.4 J/cm2. The procedure is done with the Avedro Mosaic CXL device (Avedro, Inc. Waltham, Massachusetts, United States).
Procedure: Standard crosslinking

Trial contacts and locations



Central trial contact

F.J.H.M. van den Biggelaar, PhD; Magali Vandevenne, MD

Data sourced from clinicaltrials.gov

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