Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2)

The primary objective of SCORE2 is to test for non-inferiority based on mean change from
baseline in visual acuity letter score at Month 6 for eyes randomized to intravitreal
bevacizumab every 4 weeks compared with eyes randomized to intravitreal aflibercept every 4
weeks using a non-inferiority margin of 5 letters.

Secondary objectives of SCORE2 are to:

- compare the bevacizumab and the aflibercept groups with regards to central retinal
thickness, as measured with spectral domain optical coherence tomography (SD-OCT), at
Month 6 and change between baseline and Month 6;

- assess Month 12 visual acuity and SD-OCT outcomes associated with different dosing
strategies after Month 6 in participants who respond well to treatment;

- assess Month 12 visual acuity and SD-OCT outcomes associated with alternative treatment
strategies after Month 6 in participants who respond poorly to treatment;

- compare area of retinal ischemia and rates of neovascular complications of CRVO in the
bevacizumab vs. aflibercept groups;

- add to our knowledge of the safety profile of these anti-vascular endothelial growth
factor (VEGF) medications in the setting of eyes with macular edema secondary to CRVO;

- conduct a cost effectiveness analysis comparing intravitreal bevacizumab to intravitreal
aflibercept to assess the economic implications from a payor perspective using decision
analytic methods.

Other exploratory aims of SCORE2 are to:

- investigate the correlation of features identified through SD-OCT segmentation analysis,
such as the inner segment-outer segment (IS-OS) junction (also known as the ellipsoid
zone), with such characteristics as visual acuity and central retinal thickness;

- investigate the correlation of area of peripheral retinal nonperfusion from widefield
fluorescein angiography with visual acuity and central retinal thickness, and the
prognostic value of baseline peripheral and central retina perfusion status in
predicting disease course and treatment responsiveness;

- investigate the correlation of features on adaptive optics imaging with such
characteristics as visual acuity and central retinal thickness.

Inclusion Criteria:

- Participants must have center-involved macular edema secondary to CRVO. Eyes may be
enrolled as early as the time of diagnosis of the macular edema. The definition of
CRVO used in SCORE will also be used for the purposes of SCORE2: a CRVO is defined as
an eye that has retinal hemorrhage or other biomicroscopic evidence of retinal vein
occlusion (e.g., telangiectatic capillary bed) and a dilated venous system (or
previously dilated venous system) in all 4 quadrants.

- Due to the similarities of a hemiretinal vein occlusion (HRVO) to CRVO,HRVO will be
classified as CRVO for the purposes of this clinical trial. Eyes classified as having
a HRVO will be limited to no more than 25% of the planned sample size. A HRVO is
defined as an eye that has retinal hemorrhage or other biomicroscopic evidence of
retinal vein occlusion (e.g. telangiectatic capillary bed) and a dilated venous system
(or previously dilated venous system) in 5 or more clock hours but less than all 4
quadrants. Typically, a HRVO is a retinal vein occlusion that involves 2 altitudinal
quadrants.

- E-Early Treatment Diabetic Retinopathy Study (ETDRS)visual acuity score of greater
than or equal to 19 letters (approximately 20/400) and less than or equal to 73
letters (approximately 20/40) by the ETDRS visual acuity protocol. The investigator
must believe that a study eye with visual acuity between 19 and 33 letters is
perfused.

- Retinal thickness on SD-OCT measurement, defined as central subfield thickness of 300
µm or greater. If the SD-OCT measurement is taken from a Heidelberg Spectralis
Machine, the central subfield thickness should be 320 µm or greater.

- Media clarity, pupillary dilation and participant cooperation sufficient for adequate
fundus photographs.

Exclusion Criteria:

- A condition that, in the opinion of the investigator, would preclude participation in
the study (e.g., chronic alcoholism or drug abuse, personality disorder or use of
major tranquilizers indicating difficulty in long term follow-up, likelihood of
survival of less than 12 months).

- Participation in an investigational trial within 30 days of study entry that involved
treatment with any drug that has not received regulatory approval at time of study
entry.

- History of allergy to any anti-VEGF agent, corticosteroid, or component of the
delivery vehicle.

- The participant will be moving out of the area of the clinical site to an area not
covered by another clinical site during the 12 months of the study.

- Positive urine pregnancy test: all women of childbearing potential (those who are
pre-menopausal and not surgically sterilized) may participate only if they have a
negative urine pregnancy test, and if they do not intend to become pregnant during the
timeframe of the study. Women who are sexually active with a male partner must agree
to use at least one of the following birth control methods: hormonal therapy such as
oral, implantable or injectable chemical contraceptives; mechanical therapy such as
spermicide in conjunction with a barrier such as a condom or diaphragm; intrauterine
device (IUD); or surgical sterilization of partner.

- Women who are breast-feeding.

- Examination evidence of vitreoretinal interface disease (e.g., vitreomacular traction,
epiretinal membrane), either on clinical examination or OCT thought to be contributing
to macular edema.

- An eye that, in the investigator's opinion, would not benefit from resolution of
macular edema such as eyes with foveal atrophy, dense pigmentary changes or dense
subfoveal hard exudates.

- Presence of an ocular condition that, in the opinion of the investigator, might affect
macular edema or alter visual acuity during the course of the study (e.g., age-related
macular degeneration, uveitis or other ocular inflammatory disease, neovascular
glaucoma, iris neovascularization, Irvine-Gass Syndrome, prior macula-off
rhegmatogenous retinal detachment).

- Presence of a substantial cataract that, in the opinion of the investigator, is likely
to be decreasing visual acuity by 3 lines or more (i.e., a 20/40 cataract).

- History of laser photocoagulation for macular edema within 3 months prior to
randomization.

- History of intravitreal corticosteroid within 4 months of randomization.

- Intravitreal anti-VEGF injection within 2 months of randomization. Note: Enrollment
will be limited to no more than 25% of the planned sample size with any history of
anti-VEGF treatment. Once this number of eyes has been enrolled, any history of
anti-VEGF treatment will be an exclusion criterion. For enrollment of study eyes with
prior intravitreal anti-VEGF agents, in the opinion of the investigator, the treatment
response to prior anti-VEGF treatment must be either incomplete or the study eye had
developed recurrent CRVO-associated macular edema, such that the study eye would
benefit from additional anti-VEGF treatment.

- History of peribulbar or retrobulbar corticosteroid use for any reason within 2 months
prior to randomization.

- History of panretinal scatter photocoagulation (PRP) or sector laser photocoagulation
within 3 months prior to randomization or anticipated within the next 3 months
following randomization.

- History of major ocular surgery (including cataract extraction, scleral buckle, any
intraocular surgery, etc.) within 4 months prior to randomization or anticipated
within the next 6 months following randomization.

- History of yttrium aluminum garnet (YAG) capsulotomy performed within 2 months prior
to randomization.

- Aphakia.

- Presence of an anterior chamber intraocular lens

- Examination evidence of external ocular infection, including conjunctivitis, chalazion
or significant blepharitis.

- History of macular detachment.

- Examination evidence of any diabetic retinopathy.