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

Primary Purpose

Keratoconus

Status
Recruiting
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Customized crosslinking
Standard crosslinking
Sponsored by
Maastricht University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Keratoconus focused on measuring Keratoconus, Crosslinking, Customized

Eligibility Criteria

16 Years - 45 Years (Child, Adult)All SexesDoes not accept 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

Sites / Locations

  • Maastricht University Medical Center (MUMC+)Recruiting
  • University Medical Center GroningenRecruiting
  • University Medical Center Utrecht

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Customized crosslinking

Standard crosslinking

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

Change in maximum keratometry (Kmax)
Kmax is measured with Scheimpflug photography (Pentacam® HR, OCULUS Optikgeraete GmbH, Wetzlar, Germany)

Secondary Outcome Measures

Visual acuity
Measured with ETDRS
Refraction
Change in spherical equivalent
Depth and size of demarcation line
Measured with AS OCT
Pachymetry
Measured with the Pentacam HR
Zonal Kmax
The analysis of a 3.0 mm zone centered on Kmax measured with the Pentacam HR
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.
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
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
Mean endothelial cell loss
Measured using specular microscopy photography
Rate of reepithelialisation
evaluated with fluorescein and blue light, a slit lamp image is taking to perform quantitative morphometric surface analysis
Patient Reported Outcomes Measures (PROMs)
Health-related quality of life as measured by HUI3 (Health Utility Index Mark 3) questionnaire
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)
Patient Reported Outcomes Measures (PROM)
Patient satisfaction and vision-specific quality of life as measured by Keratoconus Outcome Research Questionnaire (KORQ)
Pain after crosslinking
measured with the short form of the McGill Pain Questionnaire (SF-MPQ)
Quality Adjusted Life Years (QALYs)
Calculated based on generic health-related quality of life, using the EQ-5D-5L questionnaire
Quality Adjusted Life Years (QALYs)
Calculated based on generic health-related quality of life, using the HUI-3 questionnaire
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.
Incremental cost-effectiveness ratios (ICERs): QALY
Evaluation of cost-effectiveness by using calculated costs per quality-adjusted life years (QALYs)
Incremental cost-effectiveness ratios (ICERs): NEI VFQ-25
Calculated costs per clinically improved patient on the NEI VFQ-25 questionnaire
Incremental cost-effectiveness ratios (ICERs): Kmax
incremental healthcare costs per patient with a reduction in Kmax of ≥ 1D after crosslinking
Incremental cost-effectiveness ratios (ICERs): visual acuity
incremental healthcare costs per patient with clinical improvement in (un-) corrected distance visual acuity
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)

Full Information

First Posted
August 20, 2020
Last Updated
March 15, 2023
Sponsor
Maastricht University Medical Center
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT04532788
Brief Title
Efficacy of Customized Corneal Cross-linking vs. Standard Corneal Cross-linking
Acronym
C-CROSS
Official Title
Efficacy of Customized Corneal Cross-linking Versus Standard Corneal Cross-linking in Patients With Progressive Keratoconus
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2021 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University Medical Center
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Keratoconus
Keywords
Keratoconus, Crosslinking, Customized

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
124 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Customized crosslinking
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Standard crosslinking
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Procedure
Intervention Name(s)
Customized crosslinking
Intervention Description
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).
Intervention Type
Procedure
Intervention Name(s)
Standard crosslinking
Intervention Description
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).
Primary Outcome Measure Information:
Title
Change in maximum keratometry (Kmax)
Description
Kmax is measured with Scheimpflug photography (Pentacam® HR, OCULUS Optikgeraete GmbH, Wetzlar, Germany)
Time Frame
12 months postoperatively
Secondary Outcome Measure Information:
Title
Visual acuity
Description
Measured with ETDRS
Time Frame
at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
Title
Refraction
Description
Change in spherical equivalent
Time Frame
at baseline and 12 months postoperatively
Title
Depth and size of demarcation line
Description
Measured with AS OCT
Time Frame
at 4 weeks and 12 months postoperatively
Title
Pachymetry
Description
Measured with the Pentacam HR
Time Frame
at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
Title
Zonal Kmax
Description
The analysis of a 3.0 mm zone centered on Kmax measured with the Pentacam HR
Time Frame
at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
Title
DUCK score
Description
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.
Time Frame
at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
Title
ABCD grading system
Description
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
Time Frame
at baseline, 4 weeks, 3 months, 6 months and 12 months postoperatively
Title
Success/failure rate
Description
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
Time Frame
at 12 months postoperatively
Title
Mean endothelial cell loss
Description
Measured using specular microscopy photography
Time Frame
at 6 and 12 months postoperatively
Title
Rate of reepithelialisation
Description
evaluated with fluorescein and blue light, a slit lamp image is taking to perform quantitative morphometric surface analysis
Time Frame
4 days postoperatively
Title
Patient Reported Outcomes Measures (PROMs)
Description
Health-related quality of life as measured by HUI3 (Health Utility Index Mark 3) questionnaire
Time Frame
at baseline, 3 months, 6 months and 12 months postoperatively
Title
Patient Reported Outcomes Measures (PROM)
Description
Patient satisfaction and vision-specific quality of life as measured by National Eye Institute Visual Function Questionnaire (NEI VFQ-25)
Time Frame
at baseline, 3 months, 6 months and 12 months postoperatively
Title
Patient Reported Outcomes Measures (PROM)
Description
Patient satisfaction and vision-specific quality of life as measured by Keratoconus Outcome Research Questionnaire (KORQ)
Time Frame
at baseline, 3 months, 6 months and 12 months postoperatively
Title
Pain after crosslinking
Description
measured with the short form of the McGill Pain Questionnaire (SF-MPQ)
Time Frame
4 days postoperatively
Title
Quality Adjusted Life Years (QALYs)
Description
Calculated based on generic health-related quality of life, using the EQ-5D-5L questionnaire
Time Frame
baseline until 12 months postoperatively
Title
Quality Adjusted Life Years (QALYs)
Description
Calculated based on generic health-related quality of life, using the HUI-3 questionnaire
Time Frame
baseline until 12 months postoperatively
Title
Costs per patient
Description
Cost per patient, including valuation of resource use by using the Dutch guidelines for cost-analyses or cost prices provided by the medical center.
Time Frame
baseline until 12 months postoperatively
Title
Incremental cost-effectiveness ratios (ICERs): QALY
Description
Evaluation of cost-effectiveness by using calculated costs per quality-adjusted life years (QALYs)
Time Frame
baseline until 12 months postoperatively
Title
Incremental cost-effectiveness ratios (ICERs): NEI VFQ-25
Description
Calculated costs per clinically improved patient on the NEI VFQ-25 questionnaire
Time Frame
baseline until 12 months postoperatively
Title
Incremental cost-effectiveness ratios (ICERs): Kmax
Description
incremental healthcare costs per patient with a reduction in Kmax of ≥ 1D after crosslinking
Time Frame
baseline until 12 months postoperatively
Title
Incremental cost-effectiveness ratios (ICERs): visual acuity
Description
incremental healthcare costs per patient with clinical improvement in (un-) corrected distance visual acuity
Time Frame
baseline until 12 months postoperatively
Title
Budget impact
Description
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)
Time Frame
baseline until 12 months postoperatively

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Magali Vandevenne, MD
Phone
433877229
Ext
0031
Email
magali.vandevenne@mumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
F.J.H.M. van den Biggelaar, PhD
Phone
43877344
Ext
0031
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
R.M.M.A. Nuijts, MD, PhD
Organizational Affiliation
Department of Ophthalmology, Maastricht University Medical Center (MUMC+)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Maastricht University Medical Center (MUMC+)
City
Maastricht
State/Province
Limburg
ZIP/Postal Code
6229 HX
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
R.M.M.A Nuijts, MD, PhD
First Name & Middle Initial & Last Name & Degree
Magali Vandevenne, MD
Facility Name
University Medical Center Groningen
City
Groningen
ZIP/Postal Code
9713 GZ
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
R.J.H.J. Wijdh, MD, PhD
Facility Name
University Medical Center Utrecht
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
R.P.L. Wisse, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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