Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema
Brief 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.


Options:
A: 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.
B: Inclusion:

* Signed informed consent and authorization of use and disclosure of protected health information
* Age greater than 18 years
* Diagnosis of diabetes mellitus (type 1 or type 2) and serum HbA1c greater than 5.5% within 12 months of randomization
* Retinal thickening secondary to diabetes mellitus (diabetic macular edema) involving the center of the fovea.
* Diagnosis must be confirmed by OCT images
* Foveal thickness of greater than 250, as assessed by OCT
* Best corrected visual acuity score in the study eye of 20/40 to 20/320 inclusive (Snellen equivalents using the ETDRS protocol at a distance of 4 meters). Only one eye will be treated in the study. If both eyes are eligible, the investigator will select the eye to be enrolled. Visual acuity in the non-study eye must be greater than 20/800.
* In the opinion of the investigator, decreased vision in the study eye is due to foveal thickening from DME and not from other obvious causes.
* In the opinion of the investigator, laser photocoagulation can be withheld for at least 30 days after the patient has enrolled in the study

Exclusion Criteria:

* Panretinal photocoagulation or macular photocoagulation within 3 months of study entry in the study eye
* Use of intraocular or periocular injection of steroids in the study eye (e.g., triamcinolone) within 3 months of study entry
* Previous participation in a study and receipt of anti-angiogenic drugs (pegaptanib sodium, ranibizumab, anecortave acetate, protein kinase C inhibitor, etc.) within 2 months of study entry
* Eyes in which the investigators do not feel appropriate to do any additional laser photocoagulation
* Proliferative diabetic retinopathy in the study eye, with the exceptions of inactive, fibrotic proliferative diabetic retinopathy that has regressed following pan-retinal laser photocoagulation or tufts of neovascularization elsewhere (NVE) less than one disc area with no vitreous hemorrhage
* Vitreomacular traction or epiretinal membrane in the study eye evident biomicroscopically or by OCT
* Structural damage to the center of the macula in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), macular ischemia, or organized hard exudate plaque
* Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., age related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia)
* Concurrent disease in the study eye that could compromise visual acuity or require medical or surgical intervention during the first 6-month study period
* Eyes which are likely to need cataract surgery and intraocular lens implantation within the first 6 months of the study
* Cataract surgery in the study eye within 3 months of study entry; Yttrium-Aluminum-Garnet (YAG) laser capsulotomy within 2 months of study entry; or any other intraocular surgery within 3 months preceding Day 0.
* History of vitreoretinal surgery in the study eye within 3 months of study entry
* Uncontrolled glaucoma (defined as intraocular pressure greater than 30 mm Hg despite treatment with anti-glaucoma medications)
* Uncontrolled diabetes mellitus, as evidenced by glycosylated hemoglobin (HbA1c) value greater than 12%
* Premenopausal women not using adequate contraception
* Any women who are pregnant
* International normalized ratio (INR) greater than or equal to 3.0 (e.g. due to current treatment with warfarin). The use of aspirin or other anticoagulants is not an exclusion
* History of gastrointestinal bleeding within 2 months of study enrollment
* History of major gastrointestinal, cardiothoracic, gynecological, genitourinary, or orthopedic surgeries within 2 months of study enrollment
* History of cerebral vascular accident, myocardial infarction, transient ischemic attacks within 6 months of study enrollment
* Any patients who are on renal dialysis
C: Inclusion Criteria:

* Active, subfoveal choroidal neovascularization (CNV)
* Fibrosis \< 50% of total lesion area
* Visual acuity (VA) 20/25-20/320
* Age ≥ 50 yrs
* At least 1 drusen (\>63μ) in either eye or late AMD in fellow eye

Exclusion Criteria:

* Previous treatment for CNV in study eye
* Other progressive retinal disease likely to compromise VA
* Contraindications to injections with Lucentis or Avastin
D: Inclusion Criteria:

* Diabetic macular edema with center involvement in at least one eye
* Type 1 or type 2 diabetes mellitus diagnosed 2 years prior to screening
* Laser photocoagulation in the study eye can be withheld for at least 3 months after randomization

Exclusion Criteria:

* Patients with uncontrolled systemic or ocular diseases
* Have any history of any intraocular surgery in the study eye within the past 6 months preceding screening
* Conditions that require chronic concomitant therapy with systemic or topical ocular corticosteroids

Other protocol-defined inclusion/exclusion criteria applied to the study.

Answer: A