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

Phase 1

Completed

Interventions: Drug: 0.9% NaCl & Refresh Liquigel
Drug: Avastin® (bevacizumab)

Brief Summary: 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: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
0.9% NaCl & Refresh Liquigel	0.9% NaCl & Refresh Liquigel	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.
Avastin® (bevacizumab)	Avastin® (bevacizumab)	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Graft Failure at Week 39 and 52	12 months	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.

Secondary Outcome Measures

Name	Time	Method
Endothelial Cell Density	52 Weeks	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.