Pan-VEGF Blockade for the Treatment of Retinopathy of Prematurity (BLOCK-ROP)

January 26, 2010 updated by: Vision Research Foundation

Phase 1 Trial of Pan-VEGF Blockade for the Treatment of Retinopathy of Prematurity

Retinopathy of Prematurity (ROP) is a leading cause of blindness in children in developed countries around the world, and an increasing cause of blindness in developing countries.

The retina lines the inside of the eye. It functions as "film" within the camera which is the eye. When an infant is born prematurely, the vascular network necessary to nourish the retina has not fully developed. As a consequence, in some infants abnormal vessels proliferate instead of the normal ones - a condition known as ROP. The abnormal vessels carry scar tissue along with them, and may lead to retinal detachment and blindness if the eye is not treated.

The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study demonstrated that ablation of the peripheral avascular retina reduced the risk of poor structural and visual outcome due to retinal distortion or detachment in ROP (1980's). The ablated retina is not functional and is not amenable to regeneration.

Peripheral retinal ablation is not universally effective in fostering regression of ROP. This is particularly true for an aggressive form of ROP (aggressive posterior ROP, or APROP) which typically afflicts profoundly premature and infirm neonates. In this subset of infants, progression of ROP to bilateral retinal detachment and blindness occurs despite timely and complete peripheral retinal laser ablation.

Rationale The development of ROP is largely dependent on vascular endothelial growth factor (VEGF). When an infant is born prematurely the relatively hyperoxic environment the baby is introduced to shuts down the production of VEGF. Retinal maturation is delayed. Subsequently, at a time when intraocular VEGF levels would normally be declining late in the third trimester of pregnancy, abnormally high levels of VEGF are seen due to large areas of avascular retina and associated tissue hypoxia.

The availability of FDA-approved drugs for anti-VEGF treatment renders it possible to treat such eyes off-label. Available drugs include pegaptanib sodium (Macugen) for partial blockage of VEGF-A, or drugs such as ranibizumab (Lucentis) and bevacizumab (Avastin), which cause complete blockage of VEGF-A.

As VEGF is required in the developing retina for normal angiogenesis, and our goal is not to penetrate tissue, but to block the excessive levels of VEGF trapped within the overlying vitreous which is responsible for the abnormal vasculature in ROP.

For purposes of this study the investigators have chosen bevacizumab (Avastin), which will: a) attain complete blockage (vs. Macugen) of intravitreal VEGF-A, and; b) which is limited in its ability to penetrate tissues because it is a full antibody (vs. Lucentis, an antibody fragment specifically designed for better tissue penetration), and is more likely to restore VEGF homeostasis within the developing retina.

Study Overview

Status

Terminated

Conditions

Retinopathy of Prematurity

Intervention / Treatment

Drug: Bevacizumab

Study Type

Interventional

Enrollment (Actual)

Phase

Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Canada
- Alberta
  - Calgary, Alberta, Canada, T2S-=2H4
    - Calgary Health
United States
- California
  - Los Angeles, California, United States, 90027
    - Childrens Hospital
  - Los Angeles, California, United States, 90095
    - Jules Stein Eye Center
  - Menlo Park, California, United States, 94025
    - California Vitreoretinal Center
- Florida
  - Miami, Florida, United States, 33136
    - Bascom Palmer Eye Institute
- Georgia
  - Atlanta, Georgia, United States, 30322
    - Emory Eye Center
- Massachusetts
  - Boston, Massachusetts, United States, 02115
    - Children's Hospital / Dept. Ophthalmology
- Michigan
  - Royal Oak, Michigan, United States, 48073
    - William Beaumont Hospital
- North Carolina
  - Chapel Hill, North Carolina, United States, 27599-7040
    - University of North Carolina/Ophthalmology
- Pennsylvania
  - Philadelphia, Pennsylvania, United States, 19104
    - University of Pennsylvania/Scheie Eye Institute
- Texas
  - Houston, Texas, United States, 77030
    - Baylor College of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 months to 8 months (Child)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

Eligibility criteria

Premature newborn infants with bilateral progressive APROP despite complete peripheral retinal ablation.

Inclusion Criteria:

Inborn babies at participating NICUs (must meet inclusion criteria 3 through 7)
Outborn babies transferred to participating NICU (must meet inclusion criteria 3 through 7)
Aggressive posterior ROP
Adequate/appropriate laser ablation
Failed standard laser treatment (persistent Plus or recurrent Plus at a minimum of 1 week post-laser)
Post-menstrual age less than 36 weeks
Post-menstrual age greater than 30 weeks

Exclusion Criteria:

Fatal systemic anomaly
An ocular anomaly of one or both eyes affecting the retina or choroid
An ocular anomaly precluding use of the RetCam (eg: microphthalmia)
Neonatologist feels inclusion will unduly challenge the infant
Refusal of initial consent
Refusal of subsequent evaluation
Media opacity precluding fundus visualization (eg: cataract)
Any ocular or periocular infection(s)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: N/A
Interventional Model: Single Group Assignment
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary aim is to evaluate the safety of Bevacizumab (Avastin) administered in a single dose into the vitreous cavity. Time Frame: Weekly	Weekly

Secondary Outcome Measures

Outcome Measure	Time Frame
The secondary therapeutic study aim is to determine the efficacy of treatment with Bevacizumab (Avastin) for improving structural outcome without surgical intervention. Time Frame: Weekly	Weekly

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vision Research Foundation

Investigators

Study Chair: Michael T Trese, MD, Vision Research Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Bakri SJ, Snyder MR, Pulido JS, McCannel CA, Weiss WT, Singh RJ. Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing. Retina. 2006 May-Jun;26(5):519-22. doi: 10.1097/01.iae.0000225354.92444.7a.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2008

Primary Completion (Actual)

June 1, 2009

Study Completion (Actual)

July 1, 2009

Study Registration Dates

First Submitted

June 19, 2008

First Submitted That Met QC Criteria