Clinical trial NCT04532788: Efficacy of Customized Corneal Cross-linking vs. Standard Corneal Cross-linking
Official title: Efficacy of Customized Corneal Cross-linking Versus Standard Corneal Cross-linking in Patients With Progressive Keratoconus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Keratoconus
Keywords: Keratoconus
Crosslinking
Customized
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2020-08-31
Enrollment: 124
Sex: ALL
Minimum age (years): 16
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in maximum keratometry (Kmax)
timeFrame: 12 months postoperatively
Secondary outcomes:
measure: Visual acuity
timeFrame: at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
measure: Refraction
timeFrame: at baseline and 12 months postoperatively
measure: Depth and size of demarcation line
timeFrame: at 4 weeks and 12 months postoperatively
measure: Pachymetry
timeFrame: at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
measure: Zonal Kmax
timeFrame: at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
measure: DUCK score
timeFrame: at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
measure: ABCD grading system
timeFrame: at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
measure: Success/failure rate
timeFrame: at 12 months postoperatively
measure: Mean endothelial cell loss
timeFrame: at 6 and 12 months postoperatively
measure: Rate of reepithelialisation
timeFrame: 4 days postoperatively
measure: Patient Reported Outcomes Measures (PROMs)
timeFrame: at baseline, 3 months, 6 months and 12 months postoperatively
measure: Patient Reported Outcomes Measures (PROM)
timeFrame: at baseline, 3 months, 6 months and 12 months postoperatively
measure: Patient Reported Outcomes Measures (PROM)
timeFrame: at baseline, 3 months, 6 months and 12 months postoperatively
measure: Pain after crosslinking
timeFrame: 4 days postoperatively
measure: Quality Adjusted Life Years (QALYs)
timeFrame: baseline until 12 months postoperatively
measure: Quality Adjusted Life Years (QALYs)
timeFrame: baseline until 12 months postoperatively
measure: Costs per patient
timeFrame: baseline until 12 months postoperatively
measure: Incremental cost-effectiveness ratios (ICERs): QALY
timeFrame: baseline until 12 months postoperatively
measure: Incremental cost-effectiveness ratios (ICERs): NEI VFQ-25
timeFrame: baseline until 12 months postoperatively
measure: Incremental cost-effectiveness ratios (ICERs): Kmax
timeFrame: baseline until 12 months postoperatively
measure: Incremental cost-effectiveness ratios (ICERs): visual acuity
timeFrame: baseline until 12 months postoperatively
measure: Budget impact
timeFrame: baseline until 12 months postoperatively
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center (MUMC+)
state: Limburg
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: Department of Ophthalmology, Maastricht University Medical Center (MUMC+)
name: R.M.M.A. Nuijts, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: