Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema
Condition: Diabetic Macular Edema
MeSH terms: Macular Edema; Edema
Intervention: 2.0 mg intravitreal aflibercept; 1.25 mg intravitreal bevacizumab; 0.3 mg intravitreal ranibizumab
Intervention description: Intravitreal injection of 2.0 mg aflibercept at baseline and up to every 4 weeks using defined retreatment criteria.; Intravitreal injection of 1.25 mg bevacizumab at baseline and up to every 4 weeks using defined retreatment criteria.; Intravitreal injection of 0.3 mg ranibizumab (Lucentis™) at baseline and up to every 4 weeks using defined retreatment criteria.
Intervention MeSH terms: Bevacizumab; Ranibizumab; Aflibercept
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 660.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diabetic Macular Edema; anti-vascular endothelial growth factor

Summary:

      Although multiple studies have suggested that treatment with ranibizumab is safe and
      efficacious and superior to focal/grid laser alone for patients with center-involved diabetic
      macular edema (DME), there may be barriers in place to widespread adoption of ranibizumab use
      given its high cost per dose and the need for multiple treatments over time. Prioritizing
      resources from a public health policy perspective could be easier if more precise estimates
      regarding the risks and benefits of other anti-vascular endothelial growth factor (anti-VEGF)
      therapies were available, especially when the difference in costs could be billions of
      dollars over just a few years. Thus, there is a clear rationale at this time to explore
      potential anti-VEGF alternatives to ranibizumab that might prove to be as or more
      efficacious, might deliver equally lasting or longer-lasting treatment effects, and cost
      substantially less. Of the potentially available alternative anti-VEGF agents for this trial,
      bevacizumab and aflibercept are the best candidates for a direct comparison study.
      Bevacizumab shares the most similar molecular structure, costs far less, and is widely
      available. Furthermore, there is already preliminary evidence to suggest that it may be
      efficacious in the treatment of DME and it is already being widely used for this indication.
      Although aflibercept has a similar cost per unit dose to ranibizumab, it has the potential to
      decrease treatment burden and associated cost. If results from a comparative trial
      demonstrate improved efficacy or suggest similar efficacy of bevacizumab or aflibercept over
      ranibizumab, this information might give clinicians scientific rationale to substitute either
      one of these drugs for ranibizumab in the treatment of DME, and might thereby have
      substantial implications for public policy in terms of future estimates of health care
      dollars and possibly number of treatments necessary for anti-VEGF treatment of diabetic
      macular disease.

      Because of its availability and lower cost, bevacizumab is already currently in widespread
      clinical use for treatment of DME despite the lack of FDA approval for this indication. Thus,
      a clinical trial that suggested whether bevacizumab could be used as a safe and efficacious
      alternative to ranibizumab could substantially impact nationwide practice patterns for
      treatment of DME by either validating the current use of bevacizumab or by demonstrating
      improved outcomes with ranibizumab or aflibercept treatment for DME.

      Study Objective The primary objective of the proposed research is to compare the efficacy and
      safety of (1) intravitreal aflibercept, (2) intravitreal bevacizumab, and (3) intravitreal
      ranibizumab when given to treat central-involved DME in eyes with visual acuity of 20/32 to
      20/320.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.

          -  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 (see Procedures Manual for definitions)

          -  At least one eye meets the following study eye criteria:

               -  Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual
                  acuity letter score ≤ 78 (i.e., 20/32 or worse) and ≥ 24 (i.e., 20/320 or better)
                  within eight days of randomization.

               -  On clinical exam, definite retinal thickening due to diabetic macular edema
                  involving the center of the macula.

               -  Diabetic macular edema present on optical coherence tomography (OCT) (central
                  subfield thickness on OCT >250 µm on Zeiss Stratus or the equivalent on spectral
                  domain OCTs based on gender specific cutoffs), within eight days of
                  randomization.

               -  Investigator must verify accuracy of OCT scan by ensuring it is centered and of
                  adequate quality (for Zeiss Stratus, standard deviation of center point thickness
                  should be ≤ 10% of the center point thickness and signal strength should be ≥ 6)

               -  Media clarity, pupillary dilation, and individual cooperation sufficient for
                  adequate fundus photographs

          -  Able and willing to provide informed consent.

        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).

             •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.

          -  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.

          -  Known allergy to any component of the study drug.

          -  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.

          -  Myocardial infarction, other acute cardiac event requiring hospitalization, stroke,
             transient ischemic attack, or treatment for acute congestive heart failure within 4
             months prior to randomization.

          -  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.

          -  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.

          -  Individual is expecting to move out of the area of the clinical center to an area not
             covered by another clinical center during the first 12 months of the study.

        The following exclusions apply to the study eye only (i.e., they may be present for the
        nonstudy eye):

          -  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.

          -  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).

          -  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.).

          -  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).

          -  History of an anti-VEGF treatment for 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, intravitreal 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.

          -  History of pan-retinal photocoagulation within four months prior to randomization or
             anticipated need for pan-retinal photocoagulation in the six months following
             randomization.

          -  History of anti-VEGF treatment for a disease other than DME in the past 12 months.

          -  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.

          -  History of YAG capsulotomy performed within two months prior to randomization.

          -  Aphakia.

          -  Exam evidence of external ocular infection, including conjunctivitis, chalazion, or
             significant blepharitis.