Pan-VEGF Blockade for the Treatment of Retinopathy of Prematurity

Study Overview
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Brief Summary
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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.

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

Conditions
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Retinopathy of Prematurity

Intervention / Treatment
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* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 30 Weeks
Maximum Age: 36 Weeks

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Bevacizumab|Dosage of 0.75mg/0.03ml injectable, one time only.|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pan-Vascular Endothelial Growth Factor Blockade, Safety