Anti-VEGF Treatment for Prevention of PDR/DME

Inclusion Criteria:

1. Age >= 18 years
2. Diagnosis of diabetes mellitus (type 1 or type 2) • Any one of the following will be considered to be sufficient evidence that diabetesis present:
3. Current regular use of insulin for the treatment of diabetes
4. Current regular use of oral anti-hyperglycemia agents for the treatment ofdiabetes
5. Documented diabetes by American Diabetes Association and/or World HealthOrganization criteria
6. Able and willing to provide informed consent. Meets all of the following ocular criteria in at least one eye:
7. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visualacuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)
8. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evidenton clinical examination and on digital imaging as judged by the investigator. Readingcenter grading of less than ETDRS level 43 or greater than 53 is an exclusion. Severe NPDR is defined as:
9. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at leastas great as Standard photograph 2A, approximately 20 dot and blot hemorrhages),or
10. At least 2 fields of definite venous beading in the midperipheral quadrants or atleast 1 field at least as severe as Standard photograph 6A, or
11. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) inthe midperipheral quadrants, at least as severe as Standard photograph 8A
12. No evidence of neovascularization on clinical exam including active neovascularizationof the iris (small iris tufts are not an exclusion) or angle neovascularization (ifthe angle is assessed).
13. No evidence of neovascularization (NV) on fluorescein angiography within the 7-modified ETDRS fields, confirmed by the central Reading Center prior torandomization. • The widest method of imaging available at the site must be used to document whetherthere is NV present in the periphery; however, presence of NV outside of the 7-modified ETDRS fields on ultrawide field imaging will not be an exclusion providedtreatment is not planned.
14. No center-involved diabetic macular edema (CI-DME) on clinical exam and opticalcoherence tomography (OCT) central subfield thickness must be below the followinggender and OCT-machine specific thresholds:
15. Zeiss Cirrus: 290 µm in women and 305 µm in men
16. Heidelberg Spectralis: 305 µm in women and 320 µm in men
17. Investigator and potential participant are comfortable withholding treatment forDME until there is at least a 10% increase in OCT central subfield thickness withconfirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at twoconsecutive visits).
18. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) treatment not required AND investigator and potential participant arewilling to wait for development of high-risk characteristics (defined in protocol) totreat PDR.
19. Media clarity, pupillary dilation, and study participant cooperation sufficient toobtain adequate fundus photographs, fluorescein angiogram, and OCT.

• Investigator must verify accuracy of OCT scan by ensuring it is centered and ofadequate quality (including segmentation line placement)

Exclusion Criteria:

1. History of chronic renal failure requiring dialysis or kidney transplant.
2. A condition that, in the opinion of the investigator, would preclude participation inthe study (e.g., unstable medical status including blood pressure, cardiovasculardisease, and glycemic control).
3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.
4. Participation in an investigational trial that involved treatment within 30 days ofrandomization with any drug that has not received regulatory approval for theindication being studied. • Note: study participants cannot participate in another investigational trial thatinvolves treatment with an investigational drug while participating in the study.
5. Known allergy to any component of the study drug or any drug used in the injectionprep (including povidone iodine prep).
6. Known allergy to fluorescein dye.
7. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). • If bloodpressure is brought below 180/110 by anti-hypertensive treatment, individual canbecome eligible.
8. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. • These drugs should not be used during the study.
9. For women of child-bearing potential: pregnant or lactating or intending to becomepregnant within the next 2 years. • Women who are potential study participants should be questioned about the potentialfor pregnancy. Investigator judgment is used to determine when a pregnancy test isneeded.
10. Individual is expecting to move out of the area of the clinical center to an area notcovered by another Diabetic Retinopathy Clinical Research Network certified clinicalcenter during the next 2 years. Individual has any of the following ocular characteristics in the eye(s) being evaluated:
11. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumedto be from PDR.
12. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
13. History of prior PRP (defined as ≥100 burns outside of the posterior pole).
14. An ocular condition is present (other than diabetic retinopathy) that, in the opinionof the investigator, might alter visual acuity during the course of the study (e.g.,retinal vein or artery occlusion, uveitis or other ocular inflammatory disease,vitreomacular traction, etc.).
15. History of DME or diabetic retinopathy treatment with laser or intraocular injectionsof medication within the prior 12 months and no more than 4 prior intraocularinjections at any time in the past. • Enrollment will be limited to a maximum of 25% of the planned sample size with anyhistory of treatment for DME and/or diabetic retinopathy. Once this number of eyes hasbeen enrolled, any history of treatment for DME and/or diabetic retinopathy will be anexclusion criterion.
16. History of major ocular surgery (including cataract extraction, scleral buckle, anyintraocular surgery, etc.) within prior 4 months or anticipated within the next 6months following randomization.
17. Any history of vitrectomy.
18. History of yttrium aluminum garnet capsulotomy performed within 2 months prior torandomization.
19. Aphakia.
20. Exam evidence of severe external ocular infection, including conjunctivitis,chalazion, or substantial blepharitis.
21. Evidence of uncontrolled glaucoma.

• Intraocular pressure must be <30, with no more than one topical glaucomamedication, and no documented glaucomatous field loss for the eye to be eligible.