Using Aflibercept Injection to Treat Blood Vessel Growth Over the Cornea

Subconjunctival Aflibercept Injection for Corneal Neovascularization

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.

Study Overview

• Status: Terminated
• Conditions: Corneal Neovascularization
• Intervention / Treatment: Drug: Subconjunctival aflibercept; Other: Placebo: Standard of care only

Detailed Description

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.

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

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • John A. Moran Eye Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

A patient must meet the following criteria to be eligible for inclusion in the study:

1. Candidates for corneal transplantation (only one eye per patient would be enrolled)
2. 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
3. Willing and able to comply with clinic visits and study-related procedures
4. Provide signed informed consent
5. Age 18 or over

Exclusion Criteria:

A patient who meets any of the following criteria will be excluded from the study:

1. Patients receiving antiangiogenic anti-VEGF medication either systemically or intravitreally for other pathology or have received these drugs within 3 months of study enrollment
2. Patients with active corneal infection requiring additional treatment modalities
3. Patients receiving coumadin with INR >2.0, other anti-thrombotic agents (e.g., aspirin, Plavix) permitted at discretion of investigator
4. History of cerebrovascular accident or myocardial infarction within 6 months prior to study enrollment
5. Uncontrolled blood pressure- defined as SBP>160 mmHg or DBP >95mmHg while patient is sitting
6. Pregnant or breast-feeding women
7. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A subconjunctival aflibercept; 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; subconjunctival aflibercept injection; Other Names: EYLEA®; VEGF Trap-Eye
Placebo Comparator: Group B: Standard of care only; Patients will receive standard of care (steroids and cyclosporine) treatment only.	Other: Placebo: Standard of care only; Patients will receive standard of care (steroids and cyclosporine) treatment only.; Other Names: Standard of care

What is the study measuring?

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
Need for immunosuppression	need for immunosuppression at week 52 in both treatment groups	week 52
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
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

Collaborators and Investigators

• Sponsor: Balamurali Ambati
• Collaborators: Regeneron Pharmaceuticals
• Investigators: Principal Investigator: Balamurali Ambati, M.D., Ph.D., M.B.A., University of Utah

Publications and helpful links

General Publications

• Chang JH, Garg NK, Lunde E, Han KY, Jain S, Azar DT. Corneal neovascularization: an anti-VEGF therapy review. Surv Ophthalmol. 2012 Sep;57(5):415-29. doi: 10.1016/j.survophthal.2012.01.007.
• Chang JH, Gabison EE, Kato T, Azar DT. Corneal neovascularization. Curr Opin Ophthalmol. 2001 Aug;12(4):242-9. doi: 10.1097/00055735-200108000-00002.
• The collaborative corneal transplantation studies (CCTS). Effectiveness of histocompatibility matching in high-risk corneal transplantation. The Collaborative Corneal Transplantation Studies Research Group. Arch Ophthalmol. 1992 Oct;110(10):1392-403.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: May 15, 2013
• First Submitted That Met QC Criteria: May 29, 2013
• First Posted (Estimate): June 4, 2013

Study Record Updates

• Last Update Posted (Estimate): October 7, 2015
• Last Update Submitted That Met QC Criteria: October 5, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: transplant; cornea; graft; neovascularization
• Additional Relevant MeSH Terms: Pathologic Processes; Eye Diseases; Corneal Diseases; Metaplasia; Neovascularization, Pathologic; Corneal Neovascularization; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: AMB65110