Safety and Efficacy of Bevacizumab in High-Risk Corneal Transplant Survival

Study Overview
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Brief Summary
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The leading risk factor for corneal transplant rejection is abnormal blood vessel growth of the host bed. Vascular endothelial growth factor (VEGF) is thought to be a mediator of this corneal neovascularization (NV), therefore we would like to test the safety and efficacy of local VEGF blockade in the promotion of graft survival in high risk corneal transplants.

Detailed Description
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The purpose of this study is to test the effectiveness of a drug, bevacizumab (Avastin), in preventing blood vessels that often occur after a corneal transplantation which are considered at high-risk for rejection. In many cases these blood vessels lead to the graft rejection and eventual failure of the corneal transplant. It is hoped that this treatment will increase the chances of corneal graft survival. The medication used in this study is called bevacizumab or Avastin (Genentech, Inc). It works by inhibiting the action of a molecule called vascular endothelial growth factor (VEGF). VEGF is a substance molecule that binds to certain cells to stimulate new blood vessel formation. When VEGF is bound to the drug, it cannot stimulate the formation and growth of new blood vessels. Growth of blood vessels into the cornea is a complication which can worsen the prognosis of your corneal transplant and put the transplant at a higher risk for rejection.

Official Title
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Safety and Efficacy of Bevacizumab in High-Risk Corneal Transplant Survival

Conditions
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Corneal Neovascularization, Corneal Graft Failure

Intervention / Treatment
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* Drug: Avastin® (bevacizumab)
* Drug: 0.9% NaCl & Refresh Liquigel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Patient or legally authorized representative willing and able to provide written informed consent Willing and able to comply with study assessments for the full duration of the study High-risk characteristics for penetrating keratoplasty: Either presence of 1.) Corneal NV in one or more quadrants (≥ 3 clock hours NV ≥ 2mm from the limbus) OR 2.) Extension of corneal NV to graft-host junction in a previous failed graft In generally good stable overall health Exclusion Criteria: History of Stevens-Johnson syndrome or ocular pemphigoid Ocular or periocular malignancy Non-healing epithelial defect of at least 0.5x0.5 mm in host corneal bed lasting ≥6 weeks preoperatively Uncontrolled glaucoma Currently on dialysis Has received treatment with anti-VEGF agents (intraocular or systemic) within 45 days of study entry Concurrent use of systemic anti-VEGF agents Change in topical corticosteroid regimen within 14 days of transplantation Use of systemic immunosuppressive for indication other than corneal graft rejection Pregnancy (positive pregnancy test) or lactating Pre-menopausal women not using adequate contraception (Reliable intrauterine devices, hormonal contraception or a spermicide in combination with a barrier method) Uncontrolled hypertension defined as systolic blood pressure (BP) ≥150 or diastolic BP ≥90 mmHg History of thromboembolic event within 12 months prior to study entry Participation in another simultaneous medical investigation or trial

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Avastin® (bevacizumab)<br>Treatment will begin on Day 0, immediately upon the conclusion of the penetrating keratoplasty procedure with an injection of 0.1 milliliter (mL) (2.5 mg) bevacizumab. Starting Day 1 post-transplant surgery, subjects will begin treatment with topical bevacizumab (1% solution). Topical treatment will be self-administered 4 times a day for 4 weeks. The study treatments are to be given in addition to standard of care treatments. Also, all patients will follow a standard post-operative follow-up visit schedule. | Drug: Avastin® (bevacizumab)<br>* One time subconjunctival injection of 0.1 mL (2.5 mg) bevacizumab followed by topical treatment with 1% solution bevacizumab four times a day for four weeks.<br>* Other names: bevacizumab;|
| Placebo Comparator: 0.9% NaCl & Refresh Liquigel<br>Treatment will begin on Day 0, immediately upon the conclusion of the penetrating keratoplasty procedure with an injection of 0.1 mL 0.9% sodium chloride (NaCl). Starting Day 1 post-transplant surgery, subjects will begin treatment with topical Refresh Liquigel. Topical treatment will be self-administered 4 times a day for 4 weeks. The study treatments (both topical and subconjunctival injection) are to be given in addition to standard of care treatments. Also, all patients will follow a standard post-operative follow-up visit schedule. | Drug: 0.9% NaCl & Refresh Liquigel<br>* One-time subconjunctival injection of 0.1mL 0.9% NaCl followed by topical treatment with Refresh Liquigel four times a day for four weeks<br>* Other names: NaCL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Graft Failure at Week 39 and 52 | Time from surgery to overall graft failure (regardless of cause). Graft failure was monitored throughout the entire study, but only the time points at which graft failure occurred are reported below. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial Cell Density | Endothelial Cell Density (Assessed at Weeks 26 & 52). Measure of the number of cells present within the endothelium that are responsible for providing the cornea with nourishment. | 52 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neovascularization, High-Risk Corneal Transplantation, Penetrating Keratoplasty, Corneal Blood Vessels, Avastin, Bevacizumab, Corneal Graft