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

• Time from surgery to the occurrence of any rejection episode or overall graft failure [ Time Frame: 16, 26, and 52 weeks ] [ Designated as safety issue: No ]
• Endothelial density and central corneal thickness [ Time Frame: 16, 26, and 52 weeks ] [ Designated as safety issue: No ]
• Corneal NV metrics [ Time Frame: 16, 26, and 52 weeks ] [ Designated as safety issue: No ]

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, 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.

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.

• Drug: Avastin (bevacizumab)
  One time subconjunctival injection of 0.1mL (2.5 mg) bevacizumab followed by topical treatment with 1% solution bevacizumab four times a day for four weeks.
  Other Names:

  • Avastin
  • bevacizumab
• Drug: 0.9% NaCl & Refresh Liquigel
  One-time subconjunctival injection of 0.1mL 0.9% NaCl followed by topical treatment with Refresh Liquigel four times a day for four weeks
  Other Names:

  • Sodium Chloride
  • Refresh Liquigel
  • NaCL

• Active Comparator: Active

  Treatment will begin on Day 0, immediately upon the conclusion of the penetrating keratoplasty procedure with an injection of either 0.1mL (2.5 mg) bevacizumab. Starting Day 1 post-transplant surgery, subjects will begin treatment with either 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.

  Intervention: Drug: Avastin (bevacizumab)
• Placebo Comparator: Vehicle

  Treatment will begin on Day 0, immediately upon the conclusion of the penetrating keratoplasty procedure with an injection of 0.1mL 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.

  Intervention: Drug: 0.9% NaCl & Refresh Liquigel

Inclusion Criteria:

• Age > 18 years
• 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
• Uncontrolled glaucoma
• 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
• 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