Pretreatment to Promote Graft Survival After Subsequent High-risk Corneal Transplantation [CrossCornealVision]

Study Overview
=================
Brief Summary
-----------------
The trial evaluates the effect of corneal crosslinking as pre-treatment before corneal transplantation. The goal is to improve graft survival by reducing pathological vessels through pre-treatment.

Detailed Description
-----------------
Multicenter, two armed, controlled, open randomised parallel-group study to evaluate the effect of corneal crosslinking as pre-treatment vs. no pre-treatment ahead of full-thickness penetrating corneal transplantation. After screening of inclusion and exclusion criteria, eligible subjects will be included after obtaining informed consent. Randomisation will be performed at a 5:4 ratio. At the baseline assessment, a slit lamp examination and photo documentation as well as LaserFlareCellMeter (if available), corneal tomography, and Slit lamp Adapted Optical Coherence Tomography (SL-OCT) measurements will be performed. In addition, visual acuity and a vision-related quality of life will be assessed. In the intervention arm, the study intervention (CXL) will then be administered to reduce CoNV 10-8 weeks prior to corneal transplantation. Two weeks after CXL a control will be performed including AE documentation, slit lamp examination, SL-OCT, corneal tomography, visual acuity and photo documentation. The study intervention will be repeated once if insufficient (less than 50%) reduction of CoNV should be observed (4 weeks after first CXL at the earliest and 4 weeks prior to corneal transplantation at the latest). All subjects in the intervention arm will then be scheduled for corneal transplantation. In the control arm, subjects will be directly scheduled for corneal transplantation. Corneal transplantation will be performed as standard full-thickness penetrating procedure, and the graft (7.75 mm in diameter) will be secured with 16-24 interrupted single or double running 10-0 nylon single sutures (decision by the surgeon). Postoperatively, follow-up assessments will be performed at 3, 6, 12, 18, and 24 months for all subjects and every 6 months thereafter until the end of the trial. A slit lamp examination, AE and photo documentation as well as LaserFlareCellMeter (if available), corneal tomography, SL-OCT, and corneal endothelial cell count measurements will be performed. In addition, visual acuity and a vision-related quality of life will be assessed.

Official Title
-----------------
UV Light-mediated Corneal Crosslinking as (Lymph)Angioregressive Pretreatment to Promote Graft Survival After Subsequent High-risk Corneal Transplantation [CrossCornealVision]

Conditions
-----------------
Corneal Transplantation

Intervention / Treatment
-----------------
* Device: Corneal Crosslinking


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically prevascularized cornea with need for corneal transplantation Written informed consent by subject and/or witness/legal representative, prior to any study-related procedures Adult male and female subjects ≥ 18 years old ≥ 2 corneal quadrants covered by pathological corneal neovascularization Absence of other clinical contraindications to any part or product of the treatment plan A cooperative attitude to follow up the study procedures Exclusion Criteria: < 2 corneal quadrants covered by pathological neovascularization Corneal stromal thickness below 400 μm Active or suspected intraocular inflammation Active corneal ulceration Compromised eyelid mobility and/or symblepharon Allergy, sensitivity or intolerance to riboflavin or UV Contraindications to the local or systemic antibiotics and/or corticosteroids foreseen by the protocol Contraindications to the surgical protocol Clinically significant or unstable concurrent disease or other medical condition affecting grafting procedure Rheumatic diseases Subjects unlikely to comply with the study protocol Participation in another clinical trial where an investigational drug was received less than 4 weeks prior to screening visit Positive for human immunodeficiency virus (HIV) Known abuse of alcohol, drugs, or medicinal products Evidence of any other medical conditions (such as psychiatric illness, physical examination, or laboratory findings) that may interfere with the planned treatment, affect the subject's compliance, or place the subject at high risk of complications related to the treatment Employees of the sponsor, or employees or relatives of the investigator. Pregnant women and nursing mothers as corneal transplantation in standard care is performed under general anesthesia Persons held in an institution by legal or official order

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, multicenter, open randomized parallel-group trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Corneal Crosslinking (CXL)<br>The study intervention (CXL) will be administered to reduce CoNV 10 to 12 weeks prior to corneal transplantation. It will be repeated once if insufficient reduction of CoNV should be observed (i.e. there are still corneal neovessels present; to be decided by the respective surgeon). The second intervention will be applied 2 to 4 weeks after the first CXL and at least 4 weeks prior to transplantation). Corneal transplantation will be performed as standard full-thickness penetrating procedure, and the graft (individualized size between 6.5 to 8.25 mm in diameter) will be secured with 16-24 interrupted single or double running 10-0 nylon sutures (decision by the surgeon). In case of residual CoNV at the day of keratoplasty, fine needle diathermy will be performed using a 10/0 stainless steel needle. | Device: Corneal Crosslinking<br>* Riboflavin solution (0.1% riboflavin-5-phosphate and 20% dextran T-500) will be applied to the cornea after epithelial debridement every 2 min for 10 minutes before irradiation and every 2 minutes during the course of a 10 minute exposure to 365 nm UV-A with an irradiance rate of 9 mW/cm2. To avoid any damage to the limbal stem cells, the limbus will not be irradiated during the procedure, as a CXL device with maximal diameter of 11 mm will be used. Additionally, the limbal area will be protected by a custom-cut limbal stell cell protection shield.<br>|
| No Intervention: control group<br>Subjects will be directly scheduled for corneal transplantation without previous CXL. Corneal transplantation will be performed as standard full-thickness penetrating procedure, and the graft (individualized size between 6.5 to 8.25 mm in diameter) will be secured with 16-24 interrupted single or double running 10-0 nylon sutures (decision by the surgeon). In the control group, no fine needle diathermy will be performed, as this procedure combined with corneal transplantation in previously non-crosslinked eyes might lead to fistulas and thereby to potential intraocular infections. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First episode of endothelial graft rejection | Endothelial graft rejection episode is defined by at least 2 of the following criteria: new endothelial precipitates, new anterior chamber cells/flare, focal or diffuse new edema of the graft. All signs will be analyzed by slit lamp examination, on standardized digital slit lamp pictures, by LaserFlareCellMeter (if available), SL-OCT and corneal tomography. | within 24 months after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regression of CoNV | Regression of CoNV assessed by morphometrical analysis of the corneal area covered by CoNV using digital standardized slit lamp images and an independent reading center (CORIC) | prior to and 2-4 weeks after each CXL, prior to transplantation and at 3, 6, 12, 18 and 24 months | 
| Regression of CoNV | Number of CXL procedures needed for >50% regression of CoNV | before transplantation | 
| Recurrence of CoNV | Recurrence of CoNV after CXL and after transplantation | after CXL and 3, 6, 12, 18 and 24 months after transplantation | 
| Overall functional graft survival rate | Functional survival of graft will be assessed at every follow-up visit after transplantation clinically and using digital slit lamp pictures, SL-OCT and corneal tomography (for graft thickness) as well as endothelial cell counts. | 3, 6, 12, 18 and 24 months after transplantation | 
| Absence of rejection-related graft failure | Assessed at every follow-up visit after transplantation: defined according to the respective criteria for graft rejection and associated graft failure (yes: no evidence of endothelial graft rejection, survival of the graft OR no evidence of endothelial graft rejection, failure of the graft; no: endothelial graft rejection, failure of the graft) | 3, 6, 12, 18 and 24 months after transplantation | 
| Best corrected visual acuity (BCVA) | BCVA assessed using ETDRS charts (logMAR transformed) | Prior to CXL, prior to transplantation and after 3, 6, 12, 18, and 24 months | 
| Vision-related quality of life | Overall score measured using the NEI-VFQ25 | Prior to CXL, prior to transplantation and after 3, 6, 12, 18, and 24 months | 
| Active infectious keratitis or corneal ulceration | Clinical assessment by slit lamp examination | every study visit | 
| Graft dehiscence | Graft dehiscence with leakage of aqueous humor from the graft/host interface, assessed by slit lamp examination | 3, 6, 12, 18 and 24 months after transplantation | 
| Delayed epithelial wound healing | assessed by slit lamp examination | 3, 6, 12, 18 and 24 months after transplantation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cornea, Transplantation, Prevascularized Corneas, Corneal crosslinking with UV light irradiation