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

Phase 1

Completed

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

Brief Summary: 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: 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
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:
1. Presence of 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
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 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.
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% 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.

Primary Outcome Measures

Name	Time	Method
Endothelial Rejection Rate	12 Months	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.
Number of Participants Experiencing Ocular Adverse Events	12 months	Incidence and severity of ocular adverse events during the study (based on ophthalmic examination and subject self-reporting).
Incidence of Systemic Adverse Events	12 Months	Incidence and severity of systemic adverse events during the study (based on physical examination, subject self-reporting, and changes in vital sign).

Secondary Outcome Measures

Name	Time	Method

Locations (3): Bascom Palmer Eye Institute
🇺🇸
Miami, Florida, United States
Massachusetts Eye and Ear Infirmary
🇺🇸
Boston, Massachusetts, United States
New York Presbyterian Hospital
🇺🇸
New York, New York, United States