Study of 2.0 mg Ranibizumab in Subjects With Ischemic Central Retinal Vein Occlusion (RAVE2)

The most devastating complication of ischemic CRVO is the development of anterior segment
neovascularization and the resulting morbidity from neovascular glaucoma. This
complication appears to be directly correlated with intraocular VEGF levels. Currently
there is no proven treatment to decrease the formation of rubeosis. Current management of
the disease consists of pan-retinal photocoagulation once significant anterior segment
neovascularization becomes manifest. This treatment destroys peripheral retina (with
peripheral retinal field) and presumably works by eventually lowering ocular VEGF levels
which causes secondary regression of rubeosis.

As ranibizumab blocks VEGF, this treatment when delivered intraocularly may prevent
neo-vascular glaucoma while preserving peripheral visual fields in this patient population.

A higher dose of ranibizumab may allow for both a longer duration of treatment effect and
potentially more efficacy leading to better outcomes for patients that are somewhat
treatment resistant and need continual therapy. Nonclinical and early clinical data indicate
that higher doses of ranibizumab up to and including 2.0 mg are safe and tolerated by
patients.

Inclusion Criteria:

- Subjects will be eligible if the following criteria are met:

- Ability to provide written informed consent and comply with study assessments
for the full duration of the study

- Age > 18 years

- For patients previously treated with ITV ranibizumab (Cohort 1):

- 6 or more intravitreal injections of ranibizumab with presence of persistent
edema after a minimum of 6 ranibizumab injections followed in RAVE 1.

- For treatment naïve (Cohort 2):

- Ischemic CRVO within 3 months of enrollment as per the following inclusion
criteria

Three of the following clinical tests must be present to demonstrate ischemic CRVO:

- VA 20/200 or worse

- RAPD 0.9 LU or worse

- Loss of 1-2e isopter on Goldmann Visual field (Kwon et al. 2001)

- ERG demonstrating b wave amplitude less than 60% of A wave

- Capillary nonperfusion greater than 50 DA

Exclusion Criteria:

- Subjects who meet any of the following criteria will be excluded from this study:

- IOP over 30 mm Hg

- Any previous retinal laser photocoagulation to the study eye in treatment naive

- Any previous intravitreal injection in study eye (triamcinolone or other) in
treatment naive

- Any previous vitrectomy in study eye (posterior or anterior associated with
vitreous loss in cataract surgery)

- Intracapsular cataract extraction (posterior capsule needs to be present)

- Previous history of retinal detachment in study eye

- Any previous radiation treatments to head/ neck

- Inability to assess iris neovascularization (corneal opacity precluding
gonioscopy)

- Significant cardiovascular disease or cancer that would prevent follow-up visits
or completion of the 12 month study

- Significant diabetic retinopathy in the fellow eye (diabetic macular edema,
proliferative diabetic retinopathy, or high-risk non-proliferative diabetic
retinopathy)

- Pregnancy (positive pregnancy test)

- Participation in another simultaneous medical investigator or trial

- Ocular disorders in the study eye that may confound interpretation of study
results, including retinal detachment, macular hole, or choroidal
neovascularization of any cause (e.g., DME AMD, ocular histoplasmosis, or
pathologic myopia)

- Concurrent disease in the study eye that could compromise visual acuity or
require medical or surgical intervention during the study period

- Aphakia or absence of the posterior capsule in the study eye

- Previous violation of the posterior capsule is also excluded unless it occurred
as a result of YAG laser posterior capsulotomy in association with prior,
posterior chamber intraocular lens implantation

- History of idiopathic or autoimmune uveitis in either eye

- Structural damage to the center of the macula in the study eye preexisting to
CRVO likely to preclude improvement in visual acuity following the resolution of
macular edema, including atrophy of the retinal pigment epithelium, subretinal
fibrosis, laser scar(s)

- Vitreomacular traction or epiretinal membrane in the study eye evident
biomicroscopically or by OCT

- Ocular inflammation (including trace or above) in the study eye

- Infectious blepharitis, keratitis, scleritis, or conjunctivitis (in either eye)
or current treatment for serious systemic infection

- Spherical equivalent of the refractive error in the study eye of more than -8
diopters myopia (For patients who have had refractive or cataract surgery in the
study eye, pre-operative spherical equivalent refractive error of more than -8
diopters myopia is not allowed)

Systemic Conditions

- Uncontrolled Blood pressure exceeding diastolic pressure of 100 mm Hg (sitting)
during the screening period

- Uncontrolled diabetes mellitus

- Renal failure requiring dialysis or renal transplant

- Pregnancy (positive pregnancy test) or lactation

- Premenopausal women not using adequate contraception. The following are considered
effective means of contraception: surgical sterilization or use of oral
contraceptives, barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel, an IUD, or contraceptive hormone implant or patch.

- Any other condition that the investigator believes would pose a significant hazard to
the subject if the investigational therapy were initiated

- Participation in another simultaneous medical investigation or trial

- History of other disease, metabolic dysfunction, physical examination finding, or
other findings giving reasonable suspicion of a disease or condition that
contraindicates the use an investigational drug, might affect interpretation of the
results of the study, or render the subject at high risk from treatment complications

Other

- History of allergy to fluorescein, not amenable to treatment

- Inability to obtain fundus photographs or fluorescein angiograms of sufficient
quality to be analyzed and graded by the central reading center

- Inability to comply with study or follow up procedures

- History of allergy to humanized antibodies or any component of the ranibizumab
formulation