Efficacy of Customized Corneal Cross-linking vs. Standard Corneal Cross-linking

Study Overview
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Brief Summary
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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
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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.

Official Title
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Efficacy of Customized Corneal Cross-linking Versus Standard Corneal Cross-linking in Patients With Progressive Keratoconus

Conditions
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Keratoconus

Intervention / Treatment
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* Procedure: Customized crosslinking
* Procedure: Standard crosslinking


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Customized crosslinking<br>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<br>* 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).<br>|
| Active Comparator: Standard crosslinking<br>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<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in maximum keratometry (Kmax) | Kmax is measured with Scheimpflug photography (Pentacam® HR, OCULUS Optikgeraete GmbH, Wetzlar, Germany) | 12 months postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual acuity | Measured with ETDRS | at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively | 
| Refraction | Change in spherical equivalent | at baseline and 12 months postoperatively | 
| Depth and size of demarcation line | Measured with AS OCT | at 4 weeks and 12 months postoperatively | 
| Pachymetry | Measured with the Pentacam HR | at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively | 
| Zonal Kmax | The analysis of a 3.0 mm zone centered on Kmax measured with the Pentacam HR | at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively | 
| DUCK score | Dutch Crosslinking for Keratconus Score is based on changes in 5 clinical parameters that are routinely assessed: age, visual acuity, refraction error, keratometry, and subjective patient experience. Each items is scored from 0 to 2 and cutoffs are determined by clinical experience. | at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively | 
| ABCD grading system | Anterior radius of curvature (A), Posterior radius of curvature (B), Corneal pachymetry at thinnest point (C), Distance best corrected vision (D), and a modifier (-) for no scarring, (+) for scarring that does not obscure iris details and (++) for scarring that obscures iris details | at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively | 
| Success/failure rate | Failure is defined as progression of the disease after CXL. Progression is defined as an increase in Kmax >1D over 12 months, an increase in K1 and/or K2 >1D over 12 months and thinning and/or an increase in the rate of corneal thickness change from the periphery to the thinnest point >10% over 12 months | at 12 months postoperatively | 
| Mean endothelial cell loss | Measured using specular microscopy photography | at 6 and 12 months postoperatively | 
| Rate of reepithelialisation | evaluated with fluorescein and blue light, a slit lamp image is taking to perform quantitative morphometric surface analysis | 4 days postoperatively | 
| Patient Reported Outcomes Measures (PROMs) | Health-related quality of life as measured by HUI3 (Health Utility Index Mark 3) questionnaire | at baseline, 3 months, 6 months and 12 months postoperatively | 
| Patient Reported Outcomes Measures (PROM) | Patient satisfaction and vision-specific quality of life as measured by National Eye Institute Visual Function Questionnaire (NEI VFQ-25) | at baseline, 3 months, 6 months and 12 months postoperatively | 
| Patient Reported Outcomes Measures (PROM) | Patient satisfaction and vision-specific quality of life as measured by Keratoconus Outcome Research Questionnaire (KORQ) | at baseline, 3 months, 6 months and 12 months postoperatively | 
| Pain after crosslinking | measured with the short form of the McGill Pain Questionnaire (SF-MPQ) | 4 days postoperatively | 
| Quality Adjusted Life Years (QALYs) | Calculated based on generic health-related quality of life, using the EQ-5D-5L questionnaire | baseline until 12 months postoperatively | 
| Quality Adjusted Life Years (QALYs) | Calculated based on generic health-related quality of life, using the HUI-3 questionnaire | baseline until 12 months postoperatively | 
| Costs per patient | Cost per patient, including valuation of resource use by using the Dutch guidelines for cost-analyses or cost prices provided by the medical center. | baseline until 12 months postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): QALY | Evaluation of cost-effectiveness by using calculated costs per quality-adjusted life years (QALYs) | baseline until 12 months postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): NEI VFQ-25 | Calculated costs per clinically improved patient on the NEI VFQ-25 questionnaire | baseline until 12 months postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): Kmax | incremental healthcare costs per patient with a reduction in Kmax of ≥ 1D after crosslinking | baseline until 12 months postoperatively | 
| Incremental cost-effectiveness ratios (ICERs): visual acuity | incremental healthcare costs per patient with clinical improvement in (un-) corrected distance visual acuity | baseline until 12 months postoperatively | 
| Budget impact | Reported as a difference in costs. Different scenario's will be compared to investigate the impact of various levels of implementation (e.g. 25%, 50%, 75% of eligible patients) | baseline until 12 months postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Keratoconus, Crosslinking, Customized