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

Study Overview
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Brief Summary
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Both aflibercept and bevacizumab have been shown to improve vision in eyes with DME. In eyes with DME and at least moderate vision loss, both aflibercept and bevacizumab were also shown to be successful in many eyes. However, aflibercept was shown to be more effective at improving vision, on average, at 1 year and at 2 years. Due to the large cost difference between the two drugs, many clinicians and patients are choosing to initiate treatment with bevacizumab and then switch to aflibercept depending on the eye's response to bevacizumab treatment. However, there is no scientific evidence that this treatment strategy is as effective at improving vision as initiating treatment with aflibercept. Patients and clinicians do not know if this approach ultimately has deleterious effects on visual acuity. If starting with aflibercept is not better than starting with bevacizumab and switching to aflibercept if needed, the potential cost savings to future patients and the health care system would be substantial. However, if starting with aflibercept is better, then patients, clinicians, and health care providers can make informed decisions for how to best treat patients with DME and at least moderate vision loss. Study Objectives To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred aflibercept if needed in eyes with CI DME and moderate vision loss

Official Title
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Randomized Trial of Intravitreous Aflibercept Versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: intravitreous aflibercept
* Drug: Bevacizumab + Deferred Aflibercept Group


Participation Criteria
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Eligibility Criteria
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Participant-level Criteria Inclusion To be eligible, the following inclusion criteria must be met: 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 At least one eye meets the study eye criteria listed. Able and willing to provide informed consent. Exclusion An individual is not eligible if any of the following exclusion criteria are present: 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 or any drug used in the injection prep (including povidone iodine prep). 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. 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 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 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. 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) 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 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): 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-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. 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. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aflibercept Group<br>2.0 mg intravitreous aflibercept | Drug: intravitreous aflibercept<br>* Intravitreous aflibercept injection is made by Regeneron Pharmaceuticals, Inc. and is approved by the FDA for the treatment of neovascular age-related macular degeneration, macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular edema. Study eyes assigned to receive aflibercept will receive a dose of 2.0 mg in 0.05 cc. Aflibercept will be obtained commercially by the clinical site. The physical, chemical, and pharmaceutical properties and formulation of aflibercept are provided in the Package Insert. Intravitreous Injection Technique The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used. The injection will be performed using sterile technique<br>* Other names: Eylea;|
| Experimental: Bevacizumab + Deferred Aflibercept Group<br>1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg aflibercept if eye meets switch criteria | Drug: intravitreous aflibercept<br>* Intravitreous aflibercept injection is made by Regeneron Pharmaceuticals, Inc. and is approved by the FDA for the treatment of neovascular age-related macular degeneration, macular edema due to central retinal vein occlusion, macular edema due to branch retinal vein occlusion, diabetic macular edema, and diabetic retinopathy in eyes with diabetic macular edema. Study eyes assigned to receive aflibercept will receive a dose of 2.0 mg in 0.05 cc. Aflibercept will be obtained commercially by the clinical site. The physical, chemical, and pharmaceutical properties and formulation of aflibercept are provided in the Package Insert. Intravitreous Injection Technique The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used. The injection will be performed using sterile technique<br>* Other names: Eylea;Drug: Bevacizumab + Deferred Aflibercept Group<br>* Bevacizumab is made by Genentech, Inc. and is approved by the FDA for the treatment of metastatic colorectal cancer as well as the treatment of non-squamous non-small cell lung cancer, glioblastoma, and metastatic renal cell carcinoma. Study eyes assigned to receive bevacizumab will receive a dose of 1.25 mg provided by a single compounding pharmacy identified by the Network and distributed by the Network. The volume of the injections will be 0.05 cc. Intravitreous injection technique: The injection is preceded by a povidone iodine prep of the conjunctiva. In general, topical antibiotics in the pre-, peri-, or post-injection period should not be used. The injection will be performed using a sterile technique.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Visual Acuity | Area under the curve mean change in the electronic early treatment diabetic retinopathy study visual acuity | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in visual acuity from baseline |  | 24 weeks, 1 year, 2 years | 
| Percentages of eyes with a gain (increase) or loss (decrease) of at least 10 or at least 15 letters of visual acuity from baseline |  | 1 year, 2 years | 
| Percentages of eyes with visual acuity 20/20 or greater, 20/40 or greater, and 20/200 or worse |  | 1 year, 2 years | 
| Mean change in optical coherence tomography central subfield thickness from baseline |  | 24 weeks, 1 year, 2 years | 
| Percentage of eyes with optical coherence tomography central subfield thickness below the gender-specific spectral domain optical coherence tomography equivalent of 250 µm on Zeiss Stratus OCT |  | 1 year, 2 years | 
| Percentages of eyes with worsening or improvement of diabetic retinopathy on fundus photographs |  | 1 year, 2 years | 
| Percentage of eyes receiving panretinal photocoagulation, vitrectomy, or having vitreous hemorrhage from proliferative diabetic retinopathy |  | 1 year, 2 years | 
| Number of visits |  | 2 years | 
| Number of injections |  | 1 year, 2 years | 
| Percentage of eyes that met switch criteria (bevacizumab + deferred aflibercept group only) |  | 12, 24, 52, and 104-week visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-vascular endothelial growth factor, Diabetic Macular Edema