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

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 grow
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 multi-center 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 amendable 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 sick neonates. In this subset of
infants, progression of ROP to retinal detachments in both eyes and even blindness may occur
despite timely and complete peripheral retinal laser ablation.

RATIONALE:

The development of ROP is largely dependant on vascular endothelial growth factor (VEGF).
When an infant is born prematurely, the relatively hyperoxic environment that the baby is
introduced to shuts down the production of VEGF. Retinal maturation is thus delayed.
Subsequently, at a time when intraocular VEGF levels would 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 eye off-label. Available drugs include pegaptanib sodium (Macugen) for partial
blockage of VEGF-A, or drugs such a 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, we 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.

Inclusion Criteria:

- Inborn babies at participating NICU's who meet inclusion criteria

- Outborn babies transferred to participating NICU's who meet inclusion criteria

- Type 1 pre-threshold ROP

- No prior treatment

- Post menstrual age less than 36 1/7 weeks

- Post menstrual age greater than 30 weeks

Exclusion Criteria:

- Fatal systemic anomaly

- An ocular anomaly of one or both eye affecting the retina or choroid

- An ocular anomaly precluding use of the RetCam (ex., microphthalmia)

- Neonatologist feels inclusion will unduly challenge the infant

- Refusal of initial consent

- Refusal of subsequent evaluation

- Media opacity precluding fundus visualization (ex., cataract)

- Any ocular or periocular infection(s)