Using Aflibercept Injection to Treat Blood Vessel Growth Over the Cornea

Study Overview
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Brief Summary
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The cornea is the clear front part of the eye. Corneal neovascularization, the excessive growth of blood vessels into the cornea, is a sight-threatening condition. Corneal neovascularization is also a well recognized risk factor for corneal graft failure. The current standard of care to prevent graft rejection includes use of topical steroids and medicines that suppress the immune system. These medicines do not address corneal neovascularization. The purpose of the study is to establish the safety and potential efficacy of subconjunctival injections of aflibercept (EYLEA® , marketed by Regeneron) injection in inducing regression of blood vessels growing into the cornea and promoting graft survival. This study is being conducted by Dr. Balamurali Ambati at the Moran Eye Center.

Detailed Description
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Corneal neovascularization is a sight threatening condition and is also a well recognized risk factor for corneal graft failure. Current standard of care to prevent graft rejection includes use of topical steroids and immunosuppressants. These do not address corneal neovascularization. The cornea is kept in its avascular state by a complex interaction of signal proteins and host receptors, with a vital role played by the soluble VEGF-receptor 1. In any condition of chronic corneal inflammation or hypoxia, the balance may tip in favour of pro-angiogenic factors, and neovascularization will ensue. Early and limited studies have examined the effect of subconjunctival or intracorneal administration of monoclonal antibodies to VEGF (bevacizumab, ranibizumab) in combating corneal neovascularization. Most report subtotal or temporary regression. The development of aflibercept (also known as VEGF Trap-Eye) offers new hope of more effectively combating the problem. In this study, research will be conducted to investigate and assess safety of subconjunctival aflibercept injection in patients with corneal neovascularization undergoing corneal transplantation. This is a phase 1, prospective, randomized, open label clinical trial that will enroll 10 corneal transplant patients with corneal neovascularization in one or more quadrants crossing more than 0.5 mm over the limbus at the time of corneal transplantation.

Official Title
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Subconjunctival Aflibercept Injection for Corneal Neovascularization

Conditions
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Corneal Neovascularization

Intervention / Treatment
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* Drug: Subconjunctival aflibercept
* Other: Placebo: Standard of care only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient must meet the following criteria to be eligible for inclusion in the study: Candidates for corneal transplantation (only one eye per patient would be enrolled) Patients with corneal neovascularization in one or more quadrants crossing more than 1.0 mm over the limbus at time of enrollment in the study Willing and able to comply with clinic visits and study-related procedures Provide signed informed consent Age 18 or over Exclusion Criteria: A patient who meets any of the following criteria will be excluded from the study: Patients receiving antiangiogenic anti-VEGF medication either systemically or intravitreally for other pathology or have received these drugs within 3 months of study enrollment Patients with active corneal infection requiring additional treatment modalities Patients receiving coumadin with INR >2.0, other anti-thrombotic agents (e.g., aspirin, Plavix) permitted at discretion of investigator History of cerebrovascular accident or myocardial infarction within 6 months prior to study enrollment Uncontrolled blood pressure- defined as SBP>160 mmHg or DBP >95mmHg while patient is sitting Pregnant or breast-feeding women Sexually active men* or women of childbearing potential** who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device [IUD]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly) *Contraception is not required for men with documented vasectomy. **Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of child bearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A subconjunctival aflibercept<br>Patients will receive 2mg (0.05mL) subconjunctival aflibercept injection in addition to standard of care treatment (steroids and cyclosporine). Patients will receive one injection four weeks (+/- 1 week) prior to transplantation. They will receive a second injection at the conclusion of corneal transplantation. Patients may receive as-needed repeat injections (minimum of 30 days in between treatments) for recurrence of corneal neovascularization (defined as >1.0 mm crossing onto the cornea, past the limbus, or extension of vessels beyond previously documented extent) during the follow-up period. | Drug: Subconjunctival aflibercept<br>* subconjunctival aflibercept injection<br>* Other names: VEGF Trap-Eye;|
| Placebo Comparator: Group B: Standard of care only<br>Patients will receive standard of care (steroids and cyclosporine) treatment only. | Other: Placebo: Standard of care only<br>* Patients will receive standard of care (steroids and cyclosporine) treatment only.<br>* Other names: Standard of care;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety defined by incidence and severity of adverse events at week 28 | The primary endpoint in the study is safety as defined by incidence and severity of adverse events in patients with corneal neovascularization undergoing corneal transplant. | Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| neovascularization regression | Ability of subconjunctival aflibercept injection to regress neovascularization at time of transplant and promote graft survival after corneal transplantation | at time of transplant | 
| Need for immunosuppression | Need for immunosuppression at week 28 in both treatment groups | Week 28 | 
| Effect on corneal infections | Effect on corneal infections or other side effects through week 28 in both treatment groups | Through week 28 | 
| Change in visual acuity | Change in ETDRS visual acuity from baseline at week 28 in both treatment groups | Week 28 | 
| Mean number of injections | Mean number of injections performed per patient through week 28 in patients receiving subconjunctival aflibercept injections | Week 28 | 
| Rescue therapy | Need for rescue treatment in the standard of care group through week 28 | Week 28 | 
| neovascularization regression | Ability of subconjunctival aflibercept injection to regress neovascularization (at 28 weeks after transplant) and promote graft survival after corneal transplantation | at 28 weeks after transplant | 
| neovascularization regression | Ability of subconjunctival aflibercept injection to regress neovascularization at 52 weeks after transplant and promote graft survival after corneal transplantation | at 52 weeks after transplantation | 
| Need for immunosuppression | need for immunosuppression at week 52 in both treatment groups | week 52 | 
| Effect on corneal infections | Effect on corneal infections or other side effects through week 52 in both treatment groups. | Through week 52 | 
| Change in visual acuity | Change in ETDRS visual acuity from baseline at week 52 in both treatment groups | Week 52 | 
| Mean number of injections | Mean number of injections performed per patient through week 52 in patients receiving subconjunctival aflibercept injections | Week 52 | 
| Rescue therapy | Need for rescue treatment in the standard of care group through week 52 | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cornea, transplant, graft, neovascularization