Anti-VEGF Treatment for Prevention of PDR/DME
Condition: Diabetic Retinopathy; Diabetic Macular Edema
MeSH terms: Macular Edema; Retinal Diseases; Diabetic Retinopathy
Intervention: Prompt Sham; Prompt aflibercept; Deferred laser; Deferred aflibercept
Intervention description: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.; Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.; Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met; Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Intervention MeSH terms: Aflibercept; Endothelial Growth Factors; Mitogens
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Enrollment: 399.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: anti-vascular endothelial growth factor; nonproliferative diabetic retinopathy

Summary:

      Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative
      factor in human eye diseases characterized by neovascularization including proliferative
      diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME).
      While there is strong evidence that PDR outcomes are markedly reduced in eyes that are
      treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With
      Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes
      Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing
      during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I),
      it is unknown whether or not an earlier but less frequent dosing regimen would result in
      similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently
      would result in favorable visual acuity outcomes.

      If this study demonstrates that intravitreous aflibercept treatment is effective and safe for
      reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for
      these complications, a new strategy to prevent vision threatening complications of diabetes
      will be available for patients. The application of intravitreous aflibercept earlier in the
      course of disease (i.e., at the time when an eye has baseline severe non-proliferative
      diabetic retinopathy) could help to reduce future potential treatment burden in patients, at
      the same time resulting in similar or better long-term visual outcomes, if PDR and DME are
      prevented.

      The primary objectives of this protocol are to 1) determine the efficacy and safety of
      intravitreous aflibercept injections versus sham injections (observation) for prevention of
      PDR or CI-DME in eyes at high risk for development of these complications and 2) compare
      long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of
      disease with those that are observed initially, and treated only if high-risk PDR or CI-DME
      with vision loss develops.

      Secondary objectives include:

        -  Comparing other visual acuity outcomes between treatment groups, such as proportion of
           eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at
           least 5 letters at the consecutive study visit just before and at the 2- or 4-year visit

        -  Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT
           central subfield thickness and volume from baseline

        -  Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of
           diabetic retinopathy severity level (scale for individual eyes) by central reading
           center from baseline

        -  Comparing associated treatment and follow-up exam costs between treatment groups

        -  Comparing safety outcomes 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 and/or World Health
                  Organization criteria

          3. Able and willing to provide informed consent.

        Meets all of the following ocular criteria in at least one eye:

          1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual
             acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)

          2. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evident
             on clinical examination and on digital imaging as judged by the investigator. Reading
             center grading of less than ETDRS level 43 or greater than 53 is an exclusion.

             Severe NPDR is defined as:

               1. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least
                  as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages),
                  or

               2. At least 2 fields of definite venous beading in the midperipheral quadrants or at
                  least 1 field at least as severe as Standard photograph 6A, or

               3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in
                  the midperipheral quadrants, at least as severe as Standard photograph 8A

          3. No evidence of neovascularization on clinical exam including active neovascularization
             of the iris (small iris tufts are not an exclusion) or angle neovascularization (if
             the angle is assessed).

          4. No evidence of neovascularization (NV) on fluorescein angiography within the
             7-modified ETDRS fields, confirmed by the central Reading Center prior to
             randomization.

             • The widest method of imaging available at the site must be used to document whether
             there 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 provided
             treatment is not planned.

          5. No center-involved diabetic macular edema (CI-DME) on clinical exam and optical
             coherence tomography (OCT) central subfield thickness must be below the following
             gender and OCT-machine specific thresholds:

               1. Zeiss Cirrus: 290 µm in women and 305 µm in men

               2. Heidelberg Spectralis: 305 µm in women and 320 µm in men

               3. Investigator and potential participant are comfortable withholding treatment for
                  DME until there is at least a 10% increase in OCT central subfield thickness with
                  confirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at two
                  consecutive visits).

          6. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor
             (anti-VEGF) treatment not required AND investigator and potential participant are
             willing to wait for development of high-risk characteristics (defined in protocol) to
             treat PDR.

          7. Media clarity, pupillary dilation, and study participant cooperation sufficient to
             obtain adequate fundus photographs, fluorescein angiogram, and OCT.

               -  Investigator must verify accuracy of OCT scan by ensuring it is centered and of
                  adequate 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 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 that involved treatment within 30 days of
             randomization with any drug that has not received regulatory approval for the
             indication being studied.

             • Note: study participants cannot participate in another investigational trial that
             involves 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 injection
             prep (including povidone iodine prep).

          6. Known allergy to fluorescein dye.

          7. 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.

          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 become
             pregnant within the next 2 years.

             • 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.

         10. Individual is expecting to move out of the area of the clinical center to an area not
             covered by another Diabetic Retinopathy Clinical Research Network certified clinical
             center during the next 2 years.

        Individual has any of the following ocular characteristics in the eye(s) being evaluated:

          1. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed
             to be from PDR.

          2. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.

          3. History of prior PRP (defined as ≥100 burns outside of the posterior pole).

          4. An ocular condition is present (other than diabetic retinopathy) that, in the opinion
             of 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.).

          5. History of DME or diabetic retinopathy treatment with laser or intraocular injections
             of medication within the prior 12 months and no more than 4 prior intraocular
             injections at any time in the past.

             • Enrollment will be limited to a maximum of 25% of the planned sample size with any
             history of treatment for DME and/or diabetic retinopathy. Once this number of eyes has
             been enrolled, any history of treatment for DME and/or diabetic retinopathy will be an
             exclusion criterion.

          6. History of major ocular surgery (including cataract extraction, scleral buckle, any
             intraocular surgery, etc.) within prior 4 months or anticipated within the next 6
             months following randomization.

          7. Any history of vitrectomy.

          8. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to
             randomization.

          9. Aphakia.

         10. Exam evidence of severe external ocular infection, including conjunctivitis,
             chalazion, or substantial blepharitis.

         11. 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.