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

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.

Study Overview

• Status: Completed
• Conditions: Corneal Neovascularization; Corneal Graft Failure
• Intervention / Treatment: Drug: Avastin® (bevacizumab); Drug: 0.9% NaCl & Refresh Liquigel

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Bascom Palmer Eye Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Eye and Ear Infirmary
  • New York
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Avastin® (bevacizumab); 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.; Other Names: Avastin®; bevacizumab
Placebo Comparator: 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.	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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Reza Dana, MD
• Collaborators: United States Department of Defense; New York Presbyterian Hospital; Bascom Palmer Eye Institute

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: November 22, 2013
• First Submitted That Met QC Criteria: November 22, 2013
• First Posted (Estimate): November 27, 2013

Study Record Updates

• Last Update Posted (Actual): August 10, 2020
• Last Update Submitted That Met QC Criteria: August 6, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Corneal Neovascularization; Cornea Blood Vessels; Corneal Graft Failure; High-Risk Penetrating Keratoplasty; Corneal Transplant
• Additional Relevant MeSH Terms: Pathologic Processes; Eye Diseases; Corneal Diseases; Metaplasia; Neovascularization, Pathologic; Corneal Neovascularization; Physiological Effects of Drugs; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Laxatives; Bevacizumab; Carboxymethylcellulose Sodium
• Other Study ID Numbers: 13-113H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No