Treatment for CI-DME in Eyes With Very Good VA Study
Condition: Diabetic Macular Edema
MeSH terms: Macular Edema; Edema
Intervention: Prompt Laser; Prompt aflibercept; Deferred laser; Deferred aflibercept
Intervention description: Focal/grid laser performed at baseline and as needed during follow-up; Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria; Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met; Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria
Intervention MeSH terms: Aflibercept
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 702.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diabetic Macular Edema; anti-vascular endothelial growth factor

Summary:

      Although multiple studies have clearly demonstrated that ranibizumab therapy is more
      effective than laser alone for vision gain and avoiding vision loss in patients with
      central-involved Diabetic Macular Edema (DME), only eyes with poor visual acuity, such as a
      visual acuity letter score of 78 or worse (approximate Snellen equivalent of 20/32 or worse)
      were eligible. Eyes that have central-involved DME with "good" visual acuity (20/25 or
      better) have not been addressed systematically by recent studies for treatment of DME.
      Baseline cohort characteristics from the Early Treatment Diabetic Retinopathy Study (ETDRS)
      suggest that a substantial percentage of eyes with central-involved DME may retain good
      vision. The investigators do not know definitively whether eyes with central-involved DME and
      good vision do better with anti-VEGF (vascular endothelial growth factor) (e.g. aflibercept)
      therapy initially, or focal/grid laser treatment or observation initially followed by
      anti-VEGF only if vision worsens.

      The primary objective of the protocol is to compare the % of eyes that have lost at least 5
      letters of visual acuity at 2 years compared with baseline mean visual acuity in eyes with
      central-involved DME and good visual acuity defined as a Snellen equivalent of 20/25 or
      better (electronic-ETDRS letter score of 79 or better) that receive (1) prompt focal/grid
      photocoagulation + deferred anti-VEGF, (2) observation + deferred anti-VEGF, or (3) prompt
      anti-VEGF.

      Secondary objectives include:

        -  Comparing other visual acuity outcomes between treatment groups, such as the percent of
           eyes with at least 5, 10 and 15 letter losses in visual acuity from baseline mean visual
           acuity, percent of eyes with at least 5 letter gain in visual acuity from baseline, mean
           visual acuity, mean change in visual acuity, adjusted for baseline mean visual acuity

        -  For eyes randomized to deferred anti-VEGF, the percentage of eyes needing anti-VEGF
           treatment

        -  Comparing optical coherence tomography (OCT) outcomes, such as the mean change in OCT
           central subfield (CSF) thickness, adjusted for baseline mean thickness

        -  Comparing the number of eyes with PDR at randomization, proportion of eyes avoiding
           vitreous hemorrhage or panretinal photocoagulation (PRP) or vitrectomy for PDR between
           treatment groups

        -  Comparing safety outcomes between treatment groups

        -  Comparing associated treatment and follow-up exam costs between treatment groups
    

Eligibility criteria:

        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 diabetes is
             present:

               1. Current regular use of insulin for the treatment of diabetes

               2. Current regular use of oral anti-hyperglycemia agents for the treatment of
                  diabetes

               3. Documented diabetes by American Diabetes Association (ADA) and/or World Health
                  Organization (WHO) criteria.

          3. Able and willing to provide informed consent.

        Meets all of the following ocular criteria in at least the one eye:

          1. Best corrected E-ETDRS visual acuity letter score ≥ 79 (approximate Snellen equivalent
             20/25 or better) at two consecutive visits within 1 to 28 days.

          2. On clinical exam, definite retinal thickening due to DME involving the center of the
             macula.

          3. Diabetic macular edema confirmed on OCT (equivalent to CSF thickness on OCT ≥250
             microns on Zeiss Stratus or gender-specific spectral domain OCT equivalent) at two
             consecutive visits within 1 to 28 days.

             (a) Investigator must verify accuracy of OCT scan by ensuring it is centered and of
             adequate quality.

          4. The investigator is comfortable with the eye being randomized to any of the three
             treatment groups (observation, laser, or anti-VEGF initially).

             (a) If focal/grid photocoagulation is contraindicated because all leaking
             microaneurysms are too close to the fovea or the investigator believes the DME that is
             present will not benefit from focal/grid photocoagulation, the eye should not be
             enrolled.

          5. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate
             OCT and fundus photographs.

        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 in
             the study (e.g., unstable medical status including blood pressure, cardiovascular
             disease, 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 within 30 days of randomization that
             involved treatment with any drug that has not received regulatory approval for the
             indication being studied.

             (a) Note: study participants cannot receive another investigational drug while
             participating in the study.

          5. Known allergy to any component of the study drug.

          6. 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.

          7. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

             These drugs should not be used during the study.

          8. For women of child-bearing potential: pregnant or lactating or intending to become
             pregnant within the next 24 months.

             (a) 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.

          9. Individual is expecting to move out of the area of the clinical center to an area not
             covered by another clinical center during the 24 months of the study.

        Individual has any of the following ocular characteristics:

          1. Macular edema is considered to be due to a cause other than DME.

             a) 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 contributing to the macular edema.

          2. An ocular condition is present such that, in the opinion of the investigator, any
             visual acuity loss would not improve from resolution of macular edema (e.g., foveal
             atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition).

          3. An ocular condition is present (other than DME) 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.).

          4. Cataract is present that, in the opinion of the investigator, may alter visual acuity
             during the course of the study.

          5. Any history of prior laser or other surgical, intravitreal, or peribulbar treatment
             for DME (such as focal/grid macular photocoagulation, intravitreal or peribulbar
             corticosteroids, or anti-VEGF).

          6. History of topical steroid or nonsteroidal anti-inflammatory drugs (NSAID) treatment
             within 30 days prior to randomization.

          7. History of intravitreal or peribulbar corticosteroid within 4 months prior to
             randomization for an ocular condition other than DME.

          8. Any history of or anticipated need for intravitreal anti-VEGF within the next 6 months
             for an ocular condition other than DME (e.g. choroidal neovascularization, central
             retinal vein occlusion, PDR).

          9. History of PRP within 4 months prior to randomization or anticipated need for PRP in
             the 6 months following randomization.

         10. Any history of vitrectomy.

         11. History of major ocular surgery (cataract extraction, scleral buckle, any intraocular
             surgery, etc.) within prior 4 months or anticipated within the next 6 months following
             randomization.

         12. History of YAG capsulotomy performed within 2 months prior to randomization.

         13. Aphakia.

         14. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or
             significant blepharitis.