Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy

Proliferative diabetic retinopathy (PDR) is manifested in retinal neovascularization at the
disc (NVD) or elsewhere (NVE). Vitreous hemorrhage or tractional detachment from PDR is a
leading cause of severe visual loss and new onset blindness. Without intervention, 60 percent
of individuals with diabetic retinopathy will eventually develop PDR, resulting in
significant visual loss in nearly fifty percent.

Proliferative diabetic retinopathy is currently treated with panretinal photocoagulation
(PRP) which destroys areas of the retina but preserves central vision. PRP is most
effectively seen in a regression of new vessels, stabilization of the neovascularization, and
reduced risk of visual loss. However, the treatment is associated with unavoidable side
effects including macular edema with transient or permanent central vision loss, diminished
vision loss, and night vision loss. The treatment applies laser burns to the peripheral
retinal tissue, destroying outer photoreceptors and retinal pigment epithelium of the retina,
and is thought to exert its effect by increasing oxygen delivery to the inner retina and
decreasing viable hypoxic cells which are producing growth factors such as VEGF. Studies have
implicated vascular endothelial growth factor (VEGF) as the substance leading to
neovascularization and/or increased vascular permeability. Thus, it is reasonable to expect
that inhibition of VEGF could reduce both PDR and transient vision loss from macular edema.
There are several anti-VEGF drugs. Ranibizumab is the drug to be evaluated in this trial. In
one trial of ranibizumab on DME, ten patients with chronic DME received a series of 0.5 mg
intraocular injections. The treatments were well tolerated with no ocular or systemic adverse
events. Since intraocular injections of ranibizumab significantly reduced foveal thickness
and improved visual acuity in all ten patients, there is strong rationale to consider this
drug as adjunctive therapy to PRP in a attempt to reduce the acute, transient edema that may
occur with PRP.

Similarly, corticosteroids, a class of substances with anti-inflammatory properties, have
demonstrated to inhibit the expression of VEGF. Triamcinolone acetonide is often used as a
periocular injection for the treatment of cystoid macular edema (CME) secondary to uveitis.
Clinically, triamcinolone acetonide is used in the treatment of proliferative
vitreoretinopathy and choroidal neovascularization. Studies on patients with proliferative
diabetic retinopathy randomly assigned to receive 4 mg triamcinolone 10 to 15 days prior to
PRP treatment showed a reduction in central macular thickening, and fluorescein leakage was
greater in the injection group than in the control group at 9 and 12 months follow up. Mean
visual acuity improved by one line in the injection group and worsened by two lines in the
control group.

In summary, there is strong rationale that using either intravitreal ranibizumab or
intravitreal triamcinolone acetonide as an adjunct to PRP could reduce the magnitude of
vision loss.

This study is being conducted to determine whether intravitreal injection of an anti-VEGF
drug or an intravitreal injection of a corticosteroid can reduce the occurrence of macular
edema and visual acuity impairment following PRP. Subjects will be randomly assigned with
equal probability to one of the following three injection groups:

- Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline and 4 weeks

- Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at
4 weeks

- Sham injection at baseline and 4 weeks

The initial injection (or sham) is given on the day of randomization. Focal (macular)
photocoagulation is given 7 to 10 days following the injection. Panretinal (scatter)
photocoagulation can be initiated either on the same day as the focal photocoagulation
(immediately following the focal photocoagulation) or on a subsequent day but must be
initiated within 14 days of the baseline injection. Required follow-up visits occur at 4, 14,
34 and 56 weeks.

General Inclusion Criteria

- Age >= 18 years

- Diagnosis of diabetes mellitus (type 1 or type 2)

- Fellow eye (if not a study eye) meets criteria.

- Able and willing to provide informed consent. Study Eye Inclusion Criteria Subjects
may have one or two study eyes. Subjects with two study eyes will be randomly assigned
to receive sham injection at baseline and 4 weeks in one eye and either ranibizumab or
triamcinolone in the other eye.

- Presence of severe nonproliferative or proliferative diabetic retinopathy for which
investigator intends to complete panretinal photocoagulation within 49 days after
randomization.

- Diabetic macular edema(DME) present on clinical exam and central subfield thickness on
Optical Coherence Tomography (OCT) >250 microns, within 8 days of randomization.

- Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity
letter score >=24 (i.e., 20/320 or better), within 8 days of randomization.

- Media clarity, pupillary dilation, and subject cooperation sufficient to administer
panretinal photocoagulation and obtain adequate fundus photographs and OCT.

- If prior macular photocoagulation has been performed, the investigator believes that
the study eye may possibly benefit from additional focal photocoagulation.

General Exclusion Criteria

- Significant renal disease, defined as a history of chronic renal failure requiring
dialysis or kidney transplant.

- A condition that, in the opinion of the investigator, would preclude participation in
the study (e.g., unstable medical status including blood pressure, cardiovascular
disease, and glycemic control).

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

- Known allergy to any component of the study drugs.

- Blood pressure > 180/110 (systolic above 180 or diastolic above 110).

- Major surgery within 28 days prior to randomization or major surgery planned during
the next 6 months.

- Myocardial infarction, other cardiac event requiring hospitalization, stroke,
transient ischemic attack, or treatment for acute congestive heart failure within 4
months prior to randomization.

- Systemic anti-vascular endothelial growth factor(VEGF) or pro-VEGF treatment within 4
months prior to randomization.

- For women of child-bearing potential: pregnant or lactating or intending to become
pregnant within the next 12 months.

- Subject is expecting to move out of the area of the clinical center to an area not
covered by another clinical center during the 12 months of the study.

Study Eye Exclusion Criteria, Study eye only:

- Prior panretinal photocoagulation that was sufficiently extensive that the
investigator does not believe that at least 1200 additional burns are needed or
possible within 49 days after randomization.

- Macular edema is considered to be due to a cause other than diabetic macular edema.

- An ocular condition is present such that, in the opinion of the investigator,
preventing visual acuity loss would not improve from resolution of macular edema
(e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates,
non-retinal condition).

- An ocular condition is present (other than diabetes) that, in the opinion of the
investigator, might affect macular edema or alter visual acuity during the course of
the study (e.g., retinal vein or artery occlusion, uveitis or other ocular
inflammatory disease, neovascular glaucoma, etc.).

- Substantial cataract that, in the opinion of the investigator, is likely to be
decreasing visual acuity by 3 lines or more (i.e., cataract would be reducing acuity
to 20/40 or worse if eye was otherwise normal).

- History of treatment for DME at any time in the past 4 months (such as focal/grid
macular photocoagulation, intravitreal or peribulbar corticosteroids, anti-VEGF drugs,
or any other treatment).

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

- History of Yttrium Aluminum Garnet capsulotomy performed within 2 months prior to
randomization.

- Aphakia.

- Intraocular pressure >= 25 mmHg.

- History of open-angle glaucoma (either primary open-angle glaucoma or other cause of
open-angle glaucoma; note: angle-closure glaucoma is not an exclusion criterion).

- History of steroid-induced intraocular pressure elevation that required intraocular
pressure-lowering treatment.

- History of prior herpetic ocular infection.

- Exam evidence of ocular toxoplasmosis.

- Exam evidence of pseudoexfoliation.

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

Fellow Eye Criteria

- Intraocular pressure < 25 mmHg.

- No history of open-angle glaucoma (either primary open-angle glaucoma or other cause
of open-angle glaucoma; note: angle-closure glaucoma is not an exclusion criterion).

- No history of steroid-induced intraocular pressure elevation that required intraocular
pressure-lowering treatment.

- No exam evidence of pseudoexfoliation.