DRCR.Net Aflibercept vs. Bevacizumab + Deferred Aflibercept for the Treatment of CI-DME

Participant-level Criteria Inclusion

To be eligible, the following inclusion criteria must be met:

1. Age ≥ 18 years • Individuals <18 years old are not being included because DME is so
rare in this age group that the diagnosis of DME may be questionable.

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

- Any one of the following will be considered to be sufficient evidence that
diabetes is present:

Current regular use of insulin for the treatment of diabetes Current regular use of
oral anti-hyperglycemia agents for the treatment of diabetes Documented diabetes by
American Diabetes Association and/or World Health Organization criteria

3. At least one eye meets the study eye criteria listed.

4. Able and willing to provide informed consent.

Exclusion

An individual is not eligible if any of the following exclusion criteria are present:

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

6. 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).

- Individuals in poor glycemic control who, within the last four months, initiated
intensive insulin treatment (a pump or multiple daily injections) or plan to do
so in the next four months should not be enrolled.

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

• Note: study participants cannot receive another investigational drug while
participating in the study.

8. Known allergy to any component of the study drug or any drug used in the injection
prep (including povidone iodine prep).

9. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110).

• If blood pressure is brought below 180/110 by anti-hypertensive treatment,
individual can become eligible.

10. Systemic anti-VEGF or pro-VEGF treatment within four months prior to randomization or
anticipated use during the study.

• These drugs cannot be used during the study.

11. For women of child-bearing potential: pregnant or lactating or intending to become
pregnant within the next 24 months.

• Women who are potential study participants should be questioned about the potential
for pregnancy. Investigator judgment is used to determine when a pregnancy test is
needed.

12. Individual is expecting to move out of the area of the clinical center to an area not
covered by another clinical center during the next two years.

Study Eye Criteria The study participant must have at least one eye meeting all of the
inclusion criteria and none of the exclusion criteria listed below.

Study participants can have two study eyes only if both eyes are eligible at the time of
randomization. For study participants with two eligible eyes, the logistical complexities
of the protocol must be considered for each individual prior to randomizing both eyes.

The eligibility criteria for a study eye are as follows:

Inclusion

1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity
letter score < 69 (i.e., 20/50 or worse) and ≥ 24 (i.e., 20/320 or better) within
eight days of randomization.

2. On clinical exam, definite retinal thickening due to diabetic macular edema involving
the center of the macula.

3. Diabetic macular edema present on optical coherence tomography (OCT) within eight days
of randomization

- Zeiss Cirrus central subfield: ≥ 290µm in women or ≥ 305µm in men

- Heidelberg Spectralis central subfield: ≥ 305µm in women or ≥ 320µm in men

- Investigator must verify accuracy of OCT scan by ensuring it is centered and of
adequate quality

4. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate
fundus photographs.

Exclusions

The following exclusions apply to the study eye only (i.e., they may be present for
the nonstudy eye):

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

• An eye should not be considered eligible if: (1) the macular edema is considered to
be related to ocular surgery such as cataract extraction or (2) clinical exam and/or
OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid
or epiretinal membrane) are the primary cause of the macular edema.

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

7. 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., vein occlusion, uveitis or other ocular inflammatory disease,
neovascular glaucoma, etc.).

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

9. History of an anti-vascular endothelial growth factor (anti-VEGF) treatment for
diabetic macular edema (DME) in the past 12 months or history of any other treatment
for DME at any time in the past four months (such as focal/grid macular
photocoagulation, intravitreous or peribulbar corticosteroids).

• Enrollment will be limited to a maximum of 25% of the planned sample size with any
history of anti-VEGF treatment for DME. Once this number of eyes has been enrolled,
any history of anti-VEGF treatment for DME will be an exclusion criterion.

10. History of pan-retinal photocoagulation within four months prior to randomization or
anticipated need for pan-retinal photocoagulation in the six months following
randomization.

11. History of anti-VEGF treatment for a disease other than DME in the past 12 months.

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

13. History of YAG capsulotomy performed within two months prior to randomization.

14. Aphakia.

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

16. Evidence of uncontrolled glaucoma. • Intraocular pressure must be <30, with no more
than one topical glaucoma medication, and no documented glaucomatous field loss for
the eye to be eligible

Note, combination therapies are considered more than one medication