A Multi-Center Study of the Safety and Efficacy of Bevacizumab in High-Risk Corneal Transplant Survival

Study Overview
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Brief Summary
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The goal of this study is to investigate whether using bevacizumab (Avastin®) is both safe and effective at decreasing the likelihood of a high-risk corneal graft rejection. Patients who are high-risk for rejection have blood vessels growing from the white of the eye into the cornea (clear, front region of the eye). The medication is used at the time of surgery and in the weeks following surgery. Participants have a 50/50 chance at receiving the active study medication or a placebo medication.

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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A Multi-Center Study of the 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 Participant 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: Presence of corneal NV in one or more quadrants (≥ 3 clock hours NV ≥ 2mm from the limbus) OR 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: Quadruple


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 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% 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 |
| --- | --- | --- |
| Endothelial Rejection Rate | Endothelial rejection rates in patients in the treatment group and the control group were calculated using the Kaplan-Meier survival curve. The Kaplan-Meier/product limit estimator is a non-parametric statistical test used to show the probability of an event occurring at a given time interval. The Kaplan-Meier estimator is used to show what the probability of corneal transplant rejection (and therefore transplant survival) after administration of the active treatment or control. | 12 Months | 
| Number of Participants Experiencing Ocular Adverse Events | Incidence and severity of ocular adverse events during the study (based on ophthalmic examination and subject self-reporting). | 12 months | 
| Incidence of Systemic Adverse Events | Incidence and severity of systemic adverse events during the study (based on physical examination, subject self-reporting, and changes in vital sign). | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Corneal Neovascularization, Cornea Blood Vessels, Corneal Graft Failure, High-Risk Penetrating Keratoplasty, Corneal Transplant