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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Corneal Transplantation
• Intervention / Treatment: Device: Corneal Crosslinking

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. (Protocol V04_0 Page 37) 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. Concomitant medication will be documented. Macula OCT will be performed if deemed necessary. 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 prior to corneal transplantation at the latest). All subjects in the intervention arm will then undergo 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 (6.5 - 8.25 mm 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 (postoperative visits at these time points are standard of care). A slit lamp examination, concomitant medication, 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. Macula OCT will be performed if deemed necessary. If a subject has any complaints, he or she can contact the responsible trial site at any time.

After consultation with the investigator, additional visits can be scheduled. (Protocol V04_0 Page 50)

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Claus Cursiefen, Prof. Dr.; Phone Number: 00492214784300; Email: marie.seifert@uk-koeln.de
• Study Contact Backup: Name: Deniz Hos, Dr.; Phone Number: 004922147898896; Email: deniz.hos@uk-koeln.de

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Recruiting
    • Charité - Universitätsmedizin Berlin, Klinik für Augenheilkunde
    • Contact: Tina Dietrich-Ntoukas, PD Dr. med.; Phone Number: 004930450654419; Email: tina.dietrich-ntoukas@charite.de
    • Contact: Anna-Karina Maier-Wenzel, PD Dr. med.; Phone Number: 0049 30 450 654 419; Email: anna-karina.maier@charite.de
  • Freiburg, Germany, 79106
    • Recruiting
    • Universitätsklinikum Freiburg, Klinik für Augenheilkunde
    • Contact: Daniel Böhringer, Prof. Dr. med.; Phone Number: 0049761 270-40235; Email: Daniel.Boehringer@uniklinik-freiburg.de
    • Contact: Paola Kammrath Betancor, Dr. med.; Phone Number: 0049761 270-40235; Email: paola.kammrath.betancor@uniklinik-freiburg.de
  • Rostock, Germany, 18057
    • Recruiting
    • Klinik und Poliklinik für Augenheilkunde - Universitätsmedizin Rostock
    • Contact: Marcus Walckling, Dr. med.; Phone Number: 0049381 494 8501; Email: marcus.walckling@med.uni-rosto
    • Contact: Thomas A. Fuchsluger, Univ.-Prof. Dr. med. Dr. rer.; Phone Number: 0049381 494 8501; Email: sekretariat.uak@med.uni-rostock.de
  • Bayern
    • München, Bayern, Germany, 80336
      • Recruiting
      • Augenklinik des Klinikums der Universität München
      • Contact: Nikolaus Luft, PD Dr. med. univ. Dr. scient.; Phone Number: 0089 4400 53146; Email: nikolaus.luft@med.uni-muenchen.de
  • NRW
    • Cologne, NRW, Germany, 50937
      • Recruiting
      • University Hospital of Cologne, Centre for Ophthalmology
      • Contact: Claus Cursiefen, Professor; Phone Number: 00492214780; Email: marie.seifert@uk-koeln.de
      • Contact: Deniz Hos, PD Dr. med; Phone Number: 004922147898896; Email: deniz.hos@uk-koeln.de
    • Düsseldorf, NRW, Germany, 40225
      • Recruiting
      • Universitätsklinikum Düsseldorf, Klinik für Augenheilkunde
      • Contact: Gerd Geerling, Univ.-Prof. Dr. med; Phone Number: 004902118116051; Email: geerling@med.uni-duesseldorf.de
      • Contact: Friedrich Anton Steindor, Dr. med; Phone Number: 004902118116051; Email: FriedrichAnton.Steindor@med.uni-duesseldorf.de
  • Saarland
    • Homburg, Saarland, Germany, 66424
      • Recruiting
      • Universitätsklinikum des Saarlandes, Klinik für Augenheilkunde
      • Contact: Berthold Seitz, Prof. Dr.; Phone Number: 0049 6841 16-22387; Email: berthold.seitz@uks.eu
      • Contact: Elias Flockerzi, Dr. med.; Phone Number: 0049 6841 16-22387; Email: elias.flockerzi@uks.eu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Medical condition or disease to be investigated:

- Pathologically prevascularized cornea with need for corneal transplantation

Further inclusion criteria:

• Written informed consent by subject and/or witness 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
• In case of bilateral disease only one eye will be included
• Steroid responders with adequate control regiment or local/systemic therapy can be included

Exclusion Criteria:

• < 2 corneal quadrants covered by pathological neovascularization
• Corneal stromal thickness below 400 μm (except in the central 8 mm zone which will be replaced later by a new corneal transplant with new endothelium); peripheral stromal thinning below 400 μm in weakened recipient areas is acceptable for CXL if not affecting more than 50% of the corneal circumference (allowing for later endothelial repopulation)
• Active or suspected intraocular inflammation
• Active corneal ulceration
• Compromised eyelid mobility and/or symblepharon
• Allergy, sensitivity or intolerance to riboflavin or UV
• Contraindications, other than steroid response to the local or systemic antibiotics and/or corticosteroids (other than steroid response) foreseen by the protocol
• Contraindications to the surgical protocol
• Clinically significant or unstable concurrent disease or other medical condition affecting grafting procedure
• Rheumatic diseases treated with systemic immunosuppressive medication
• Subjects unlikely to comply with the study protocol or unable to understand the nature and scope of the study or the possible benefits or unwanted effects of the study procedures and treatments
• 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 anaesthesia
• Persons held in an institution by legal or official order
• Dysregulated glaucoma with IOP > 25 mmHg at baseline despite local therapy

(Protocol V04_0 Page 43)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Corneal Crosslinking (CXL); In the intervention group, the study intervention (CXL) will be administered to stabilize therecipient cornea (which remains in place after penetrating keratoplasty) and to reduce CoNV 8 to 10 weeks prior to corneal transplantation. The study intervention will be repeated once (after 4 weeks prior to transplantation at the latest at the earliest) if insufficient (less than 50%) reduction of CoNV should be observed (to be decided by the respective surgeon). (Protocol V04_0 Page 45) Corneal transplantation will be performed as standard full-thickness penetrating procedure, and the graft (6.5 to 8.25 in diameter) will be secured with 16-24 interrupted single or 2 double running 10-0 nylon sutures (decision by the surgeon). In case of residual CoNV in the intervention group, visible vessels will may be thermally occluded by fine needle diathermy to avoid intraoperative bleeding and reduce complications (to be decided by the respective surgeon at start of surgery). (Protocol V04_0 Page 46)	Device: Corneal Crosslinking; Riboflavin isotonic, 0,1 % Vitamin B2, with Dextran 20,0%, for epi-off procedure or Riboflavin isotonic 0,1% (Vitamin B2), 1,1% HPMC without Dextran for epi-off) 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. This dose, mode and scheme of the intervention follows the internationally recognized "accelerated CXL protocol" (Elbaz et al. 2014). The data existing shows equivalent outcome regarding efficacy and safety compared to the standard protocol. 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. Furthermore, the limbal area will additionally be protected by a custom-cut LSC protection shield. (Protocol V04_0 Page 45-46)
No Intervention: control group; In the control group subjects will be directly scheduled for corneal transplantation without previous CXL. A sham CXL procedure will not be performed. Corneal transplantation will be performed as standard full-thickness penetrating procedure, and the graft (6.5 to 8.25 in diameter) will be secured with 16-24 interrupted single or 2 double running 10-0 nylon sutures (decision by the surgeon). In case of residual CoNV in the intervention group, visible vessels will may be thermally occluded by fine needle diathermy to avoid intraoperative bleeding and reduce complications (to be decided by the respective surgeon at start of surgery). 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. (Protocol V04_0 Page 46)

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, new focal or diffuse 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. (Protocol V04_0 Page 48)	within 24 months after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regression of CoNV	Number of CXL procedures needed for >50% regression of CoNV	before transplantation
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
Regression of CoNV	Assessed by morphometrical analysis of the corneal area covered by CoNV prior to and 2-4 weeks after each CXL, prior to transplantation and at 3, 6, 12, 18 and 24 months using digital standardized slit lamp images and an independent reading center (CORIC). Note: the corneal area covered by CoNV will also be measured in control patients (not receiving angioregressive CXL) at all visits to determine the natural course of CoNV. (Protocol V04_0 Page 48)	prior to and 2-4 weeks after each CXL, prior to transplantation and at 3, 6, 12, 18 and 24 months
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	Rejection-related graft failure assessed at every follow-up visit after transplantation and defined according to the respective criteria for graft rejection and associated graft failure	3, 6, 12, 18 and 24 months after transplantation
Best corrected visual acuity (BCVA)	Best corrected visual acuity (BCVA) in the study eye and BCVA or spectacle corrected visual acuity in the partner eye: assessed at the following time-points: prior to CXL, at control visit after CXL, prior to transplantation and after 3, 6, 12, 18, and 24 months 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 composite score measured using the NEI-VFQ25 at the following time-points	Prior to CXL, prior to transplantation and after 3, 6, 12, 18, and 24 months

Collaborators and Investigators

• Sponsor: Claus Cursiefen
• Collaborators: German Federal Ministry of Education and Research; Uniklinik Köln, Zentrum für Klinische Studien; Uniklinik Köln, Institut für Medizinische Statistik und Bioinformatik
• Investigators: Principal Investigator: Claus Cursiefen, Prof. Dr., University Hospital of Cologne, Centre for Ophthalmology

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2023
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: May 3, 2023
• First Submitted That Met QC Criteria: May 21, 2023
• First Posted (Actual): May 23, 2023

Study Record Updates

• Last Update Posted (Actual): October 21, 2024
• Last Update Submitted That Met QC Criteria: October 17, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Transplantation; Cornea; Prevascularized Corneas; Corneal crosslinking with UV light irradiation
• Other Study ID Numbers: Uni-Koeln-5045; 01KG2127 (Other Grant/Funding Number: German Federal Ministry of Education and Research (BMBF))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No