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

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)

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)