Corneal Graft Failure, Corneal Neovascularization
Conditions
Keywords
Corneal Neovascularization, Cornea Blood Vessels, Corneal Graft Failure, High-Risk Penetrating Keratoplasty, Corneal Transplant
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.
Interventions
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.
One-time subconjunctival injection of 0.1mL 0.9% NaCl followed by topical treatment with Refresh Liquigel four times a day for four weeks.
Sponsors
United States Department of Defense
Bascom Palmer Eye Institute
New York Presbyterian Hospital
Reza Dana, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 39 |
| 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.
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. | 36 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 2 |
| Overall Study | Physician Decision | 1 | 1 |
Baseline characteristics
| Characteristic | 0.9% NaCl & Refresh Liquigel | Total | Avastin® (Bevacizumab) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 39 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 36 Participants | 21 Participants |
| Age, Continuous | 65.4 years STANDARD_DEVIATION 16 | 65 years STANDARD_DEVIATION 15 | 63.5 years STANDARD_DEVIATION 13.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 25 Participants | 47 Participants | 22 Participants |
| Region of Enrollment United States | 36 participants | 74 participants | 38 participants |
| Sex: Female, Male Female | 17 Participants | 35 Participants | 18 Participants |
| Sex: Female, Male Male | 19 Participants | 40 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 36 |
| other Total, other adverse events | 34 / 39 | 35 / 36 |
| serious Total, serious adverse events | 2 / 39 | 4 / 36 |
Outcome results
Primary
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.
Time frame: 12 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avastin® (Bevacizumab) | Endothelial Rejection Rate | 2 Participants |
| 0.9% NaCl & Refresh Liquigel | Endothelial Rejection Rate | 5 Participants |
Comparison: 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.p-value: 0.195% CI: [0.12, 1.14]Log Rank
Primary
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).
Time frame: 12 Months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avastin® (Bevacizumab) | Incidence of Systemic Adverse Events | Incidence of Systemic Adverse Events | 34 Participants |
| Avastin® (Bevacizumab) | Incidence of Systemic Adverse Events | Incidence of Mild Systemic Adverse Events | 10 Participants |
| Avastin® (Bevacizumab) | Incidence of Systemic Adverse Events | Incidence of Moderate Systemic Adverse Events | 2 Participants |
| Avastin® (Bevacizumab) | Incidence of Systemic Adverse Events | Incidence of Severe Systemic Adverse Events | 2 Participants |
| 0.9% NaCl & Refresh Liquigel | Incidence of Systemic Adverse Events | Incidence of Severe Systemic Adverse Events | 1 Participants |
| 0.9% NaCl & Refresh Liquigel | Incidence of Systemic Adverse Events | Incidence of Systemic Adverse Events | 36 Participants |
| 0.9% NaCl & Refresh Liquigel | Incidence of Systemic Adverse Events | Incidence of Moderate Systemic Adverse Events | 1 Participants |
| 0.9% NaCl & Refresh Liquigel | Incidence of Systemic Adverse Events | Incidence of Mild Systemic Adverse Events | 6 Participants |
p-value: 0.2495% CI: [0.79, 1.02]Fisher Exact
Comparison: The number of mild systemic Adverse Events for subjects in intervention group (Avastin® (bevacizumab) and control group (0.9% NaCl \& Refresh Liquigel) were counted and compared.p-value: 0.495% CI: [0.68, 3.9]Fisher Exact
Comparison: The number of moderate severity systemic Adverse Events for subjects in intervention group (Avastin® (bevacizumab) and control group (0.9% NaCl \& Refresh Liquigel) were counted and compared.p-value: >0.9995% CI: [0.26, 14.5]Fisher Exact
Comparison: The number of severe systemic Adverse Events for subjects in intervention group (Avastin® (bevacizumab) and control group (0.9% NaCl \& Refresh Liquigel) were counted and compared.p-value: >0.9995% CI: [0.26, 14.5]Fisher Exact
Primary
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).
Time frame: 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avastin® (Bevacizumab) | Number of Participants Experiencing Ocular Adverse Events | Incidence of Ocular Adverse Events | 34 Participants |
| Avastin® (Bevacizumab) | Number of Participants Experiencing Ocular Adverse Events | Incidence of Mild Ocular Adverse Events | 21 Participants |
| Avastin® (Bevacizumab) | Number of Participants Experiencing Ocular Adverse Events | Incidence of Moderate Ocular Adverse Events | 8 Participants |
| Avastin® (Bevacizumab) | Number of Participants Experiencing Ocular Adverse Events | Incidence of Severe Ocular Adverse Events | 4 Participants |
| 0.9% NaCl & Refresh Liquigel | Number of Participants Experiencing Ocular Adverse Events | Incidence of Severe Ocular Adverse Events | 6 Participants |
| 0.9% NaCl & Refresh Liquigel | Number of Participants Experiencing Ocular Adverse Events | Incidence of Ocular Adverse Events | 35 Participants |
| 0.9% NaCl & Refresh Liquigel | Number of Participants Experiencing Ocular Adverse Events | Incidence of Moderate Ocular Adverse Events | 8 Participants |
| 0.9% NaCl & Refresh Liquigel | Number of Participants Experiencing Ocular Adverse Events | Incidence of Mild Ocular Adverse Events | 21 Participants |
Comparison: The incidence of Ocular Adverse Events for subjects in intervention group (Avastin® (bevacizumab) and control group (0.9% NaCl \& Refresh Liquigel) were counted and compared.p-value: 0.3695% CI: [0.78, 1.06]Fisher Exact
Comparison: The number of mild severity Ocular Adverse Events for subjects in intervention group (Avastin® (bevacizumab) and control group (0.9% NaCl \& Refresh Liquigel) were counted and compared.p-value: 0.8295% CI: [0.63, 1.4]Fisher Exact
Comparison: The number of moderate severity Ocular Adverse Events for subjects in intervention group (Avastin® (bevacizumab) and control group (0.9% NaCl \& Refresh Liquigel) were counted and compared.p-value: >0.9995% CI: [0.41, 2.2]Fisher Exact
Comparison: Severe ocular adverse events for subjects in intervention group and control group were counted and compared.p-value: 0.5195% CI: [0.2, 1.9]Fisher Exact